EMA, MCD, PEM, PUM, KL-6, MAM6, MCKD, PEMT, CD227, H23AG, MCKD1, MUC-1, ADMCKD, ADMCKD1, CA 15-3, MUC-1/X, MUC1/ZD, MUC-1/SEC
This gene encodes a membrane-bound protein that is a member of the mucin family. Mucins are O-glycosylated proteins that play an essential role in forming protective mucous barriers on epithelial surfaces. These proteins also play a role in intracellular signaling. This protein is expressed on the apical surface of epithelial cells that line the mucosal surfaces of many different tissues including lung, breast stomach and pancreas. This protein is proteolytically cleaved into alpha and beta subunits that form a heterodimeric complex. The N-terminal alpha subunit functions in cell-adhesion and the C-terminal beta subunit is involved in cell signaling. Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas. This gene is known to contain a highly polymorphic variable number tandem repeats (VNTR) domain. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2011]
MUC1 is implicated in: - apical plasma membrane
- cell surface
- cellular protein metabolic process
- DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
- DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator
- extracellular region
- Golgi lumen
- integral to plasma membrane
- negative regulation of apoptotic process
- negative regulation of transcription by competitive promoter binding
- nuclear chromatin
- O-glycan processing
- p53 binding
- positive regulation of histone H4 acetylation
- positive regulation of transcription from RNA polymerase II promoter in response to stress
- post-translational protein modification
- protein binding
- regulation of transcription from RNA polymerase II promoter in response to stress
- RNA polymerase II core promoter proximal region sequence-specific DNA binding
- transcription cofactor activity
Data from Gene Ontology via CGAP [Hide]
MUC1 is sometimes involved in t(1;14) translocations in Non Hodgkin's Lymphoma, but otherwise there aren't many reports of the gene being regularly mutated in cancer. However, MUC1 protein is overexpressed in a diverse range of carcinomas and expression of MUC1 is a prognostic factor in several types of cancer. Expression of MUC1 can play an important role in the development of resistance to chemotherapy. Also, MUC1 expression in cancer cells is associated with avoidance of immune defenses (e.g. Suzuki et al, 2012) and MUC1 can bind to p53 resulting in inhibition of p53-mediated apoptosis (Wei et al, 2005). Increased expression of MUC1 also promotes cancer cell mobility promoting the formation of metastases (Schroeder et al, 2003). MUC1 is a potential target for immunotherapy.
Graph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.
MUC1 Expression in Breast CancerPrognostic High levels of MUC1 protein are expressed in >70% of breast cancers.
In a series of 691 patients Sinn et al (2013) found high levels of MUC1 were more frequent in hormone-receptor-positive breast cancers and that MUC1 protein and mRNA expression were independently prognostic for overall survival in multivariate analysis.
MUC1 and ImmunotherapyTherapy Since its discovery MUC1 has been an attractive target for antitumor immunotherapy (e.g. Karanikas et al, 1997) - in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 and vaccination strategies have been developed and are now being tested in clinical trials against different types of cancer (Roulois et al (2013) [Full Text])
MUC1 overexpression in Pancreatic CancerPrognostic MUC1 is overexpressed in >60% of human pancreatic cancers, and is associated with poor prognosis, enhanced metastasis and chemoresistance - (Nath et al (2013)) reported that pancreatic cancers with high levels of MUC1 were associated with increased drug resistance, and suggest that MUC1 plays a role in upregulating MRP1, a protein involved in drug resistance.
MUC1 and Lung CancerPrognostic Hirasawa et al (2000) found that levels of anti-MUC1 antibody in serium was a significant prognostic factor for Non-Small Cell Lung Cancer (NSCLC). Situ et al (2011) evaluated the expression of MUC1 in 178 stage IB NSCLC and found that high MUC1 expression was more common in adenocarcinomas than squamous cell carcinomas. Up-regulated expression of MUC1 was a significant adverse prognostic factor for survival and disease-free survival in both univariate and multivariate analysis.
MUC1 and Colorectal CancerPrognostic MUC1 expression was associated with advanced disease and poor prognosis in a number of studies. For example Duncan et al (2007) found MUC1 expression was an independent prognostic factor in a series of 462 colorectal cancer patients, even when vascular invasion was included in multivariate analysis.
MUC1 and Gastric Cancer There are some conflicting results about the clinical relevance of MUC1 expression in gastric carcinoma in the literature. Some studies report MUC1 expression levels are associated with tumor cell differentiation, lymph note involvement and distant metastases. Ilhan et al. (2010) notes that MUC1 is strongly expressed in normal gastric epithelium. There are also reports linking polymorphisms in MUC1 to susceptibility to gastric cancer.
MUC1 and Bladder Cancer Simms et al (1999) and some other subsequent studies found that whilst serum MUC1 is not as useful tumour marker for screening/diagnosis of bladder cancer, levels are higher in advanced disease. Suzuki et al (2012) reported that binding of galectin-3 to poly-N-acetyllactosamine in MUC1 core 2 O-glycans reduces the interaction with Natural Killer (NK) cells and interferes with the access of tumor necrosis factor-related apoptosis-inducing ligand to C2GnT-expressing bladder cancer cells. This enables tumor cells to evade NK cell immunity and survive longer in blood circulation, thereby metastasis.
MUC1 polymorphisms and cancer suseptability? Mitsuta et al (2005) found that a large MUC1 allele was associated with susceptibility to lung adenocarcinoma and poor prognosis based on a study of 52 NSCLC patients in Japan compared to 52 controls. Xu et al (2009) reported that risk of gastric cancer is associated with the MUC1 568 A/G polymorphism. Li et al (2012) reported a protective effect of the rs2070803 polymorphism in MUC1 in a case-control study of 300 Chinese gastric cancer patients and 300 controls. In a a genome-wide association study Saeki et al (2013) reported polymorphisms in MUC1 and PSCA (8q24) were linked to diffuse-type gastric cancer in a Japanese population.
Atlas of Genetics and Cytogenetics in Oncology and Haematology
MUC1 OMIM, Johns Hopkin University Referenced article focusing on the relationship between phenotype and genotype.
MUC1 International Cancer Genome Consortium. Summary of gene and mutations by cancer type from ICGC
MUC1 Cancer Genome Anatomy Project, NCI Gene Summary
MUC1 COSMIC, Sanger Institute Somatic mutation information and related details
MUC1 GEO Profiles, NCBI Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MUC1 (cancer-related)
Rudnicka K, Backert S, Chmiela M Genetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences. Curr Top Microbiol Immunol. 2019; 421:53-76 [PubMed] Related Publications
Helicobacter pylori infection is associated with the development of a chronic inflammatory response, which may induce peptic ulcers, gastric cancer (GC), and mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic H. pylori infection promotes the genetic instability of gastric epithelial cells and interferes with the DNA repair systems in host cells. Colonization of the stomach with H. pylori is an important cause of non-cardia GC and gastric MALT lymphoma. The reduction of GC development in patients who underwent anti-H. pylori eradication schemes has also been well described. Individual susceptibility to GC development depends on the host's genetic predisposition, H. pylori virulence factors, environmental conditions, and geographical determinants. Biological determinants are urgently sought to predict the clinical course of infection in individuals with confirmed H. pylori infection. Possible candidates for such biomarkers include genetic aberrations such as single-nucleotide polymorphisms (SNPs) found in various cytokines/growth factors (e.g., IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFN-γ, TNF, TGF-β) and their receptors (IL-RN, TGFR), innate immunity receptors (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1) as well as glycoproteins (MUC1, PSCA), and DNA repair enzymes (ERCC2, XRCC1, XRCC3). Bacterial determinants related to GC development include infection with CagA-positive (particularly with a high number of EPIYA-C phosphorylation motifs) and VacA-positive isolates (in particular s1/m1 allele strains). The combined genotyping of bacterial and host determinants suggests that the accumulation of polymorphisms favoring host and bacterial features increases the risk for precancerous and cancerous lesions in patients.
Hussein HAM, Alfhili MA, Pakala P, et al. miRNAs and their roles in KSHV pathogenesis. Virus Res. 2019; 266:15-24 [PubMed] Related Publications
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman Disease (MCD). Recent mechanistic advances have discerned the importance of microRNAs in the virus-host relationship. KSHV has two modes of replication: lytic and latent phase. KSHV entry into permissive cells, establishment of infection, and maintenance of latency are contingent upon successful modulation of the host miRNA transcriptome. Apart from host cell miRNAs, KSHV also encodes viral miRNAs. Among various cellular and molecular targets, miRNAs are appearing to be key players in regulating viral pathogenesis. Therefore, the use of miRNAs as novel therapeutics has gained considerable attention as of late. This innovative approach relies on either mimicking miRNA species by identical oligonucleotides, or selective silencing of miRNA with specific oligonucleotide inhibitors. Here, we provide an overview of KSHV pathogenesis at the molecular level with special emphasis on the various roles miRNAs play during virus infection.
Saqafi B, Rahbarizadeh F Polyethyleneimine-polyethylene glycol copolymer targeted by anti-HER2 nanobody for specific delivery of transcriptionally targeted tBid containing construct. Artif Cells Nanomed Biotechnol. 2019; 47(1):501-511 [PubMed] Related Publications
The present research seeks to investigate the process of mixing targeted gene delivery and transcriptional targeting. We have conjugated Polyethylenimine polymers (PEI) and molecules of poly (ethylene glycol). The next step was covalent attachment of anti-HER2 variables domains of camelid heavy chains antibodies (VHHs) or nanobodies (Nbs) to the distal terminals of NHS-PEG3500 in PEI-PEG nanoparticles. The whole procedure yielded PEI-PEG-Nb immunoconjugates. Having determined the properties of polyplexes, steps were taken to investigate the most efficient ratio of PEI polymers to pDNA molecules (N/P) so that the greatest rate of transfection may be obtained. This immune targeted nano biopolymer could condense the gene constructs that coded a transcriptionally targeted truncated -Bid (tBid) killer gene which was controlled by the breast cancer-specific MUC1 promoter. The favourable physicochemical properties matching both the size and zeta potential were observed in engineered polyplexes. Elevated transfection efficiency in HER2 positive cell lines using Nb-modified polyplexes were shown by the results of flow cytometry as compared against non-modified particles. 1.6 and 4.8 fold higher transfection efficiencies were observed in in vitro gene expression researches which used PEI-PEG-Nb/pGL4.50 compared to the situation when native PEI polymers were utilized in both BT-474 and SK-BR-3, respectively. A 2.22 and 3.62 fold rise in the level of tBid gene expression in BT-474 and SK-BR-3 cell lines relative to unmodified PEI treated cells was the result of transfection with PEI-PEG-Nb/pMUC1-tBid, respectively. In those HER2-positive cells which were transfected by targeted polyplexes, higher levels of cell death were observed. This fact points not only to the effective targeted delivery, but it is also indicative of transcriptional targeting efficiency of tBid killer gene when its expression is controlled by MUC1 promoter.
BACKGROUND: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. METHODS: To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. RESULTS: We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1. To further investigate the role of BAP1, we used our recently developed cancer driver gene prioritization algorithm, HIT'nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. CONCLUSIONS: Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.
Kojima Y, Tanabe M, Kato I, et al. Myoepithelioma-like tumor of the vulvar region showing infiltrative growth and harboring only a few estrogen receptor-positive cells: A case report. Pathol Int. 2019; 69(3):172-176 [PubMed] Related Publications
Recently, a new entity "myoepithelioma-like tumor of the vulvar region (MELTVR)" was proposed as a rare mesenchymal neoplasm arising in vulvar regions of adult women. While MELTVRs morphologically resemble soft tissue myoepitheliomas and extraskeletal myxoid chondrosarcomas, they have a unique immunohistochemical profile (positive for epithelial membrane antigen and estrogen receptor, negative for S100 protein and glial fibrillary acidic protein, and loss of INI1/SMARCB1 expression), and lack EWSR1 and NR4A3 gene rearrangement, as seen by fluorescence in situ hybridization. MELTVRs are usually well-demarcated tumors, with no reports of extensive infiltrative growth. In the current report, we present an unusual case of MELTVR showing infiltrative growth and harboring only a few estrogen receptor-positive cells, which might indicate a variation in this rare tumor.
Esophageal cancer is the eighth most common form of cancer worldwide, and esophageal squamous cell carcinoma (ESCC) is a major type of esophageal cancer that arises from epithelial cells of the esophagus. Local lymph node metastasis (LNM) is a typical sign of failure for ESCC clinical treatments, and a link has been established between LNM and the aberrant expression of specific biomarkers. In this review, we summarize what is known about nine factors significantly associated with LNM in ESCC patients: phosphatase and tensin homolog (PTEN), mucin 1, vascular endothelial growth factor-C, tumor necrosis factor alpha-induced protein 8 (TNFAIP8), Raf-1 kinase inhibitory protein, stathmin (STMN1), metastasis-associated protein 1, caveolin-1, and interferon-induced transmembrane protein 3. The function of these nine proteins involves four major mechanisms: tumor cell proliferation, tumor cell migration and invasion, epithelium-mesenchymal transition, and chemosensitivity. The roles of PTEN, STMN1, and TNFAIP8 involve at least two of these mechanisms, and we suggest that they are possible biomarkers for predicting LNM in ESCC. However, further retrospective research into PTEN, STMN1, and TNFAIP8 is needed to test their possibilities as indicators.
Lee HK, Kwon MJ, Seo J, et al. Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in ALK-positive lung cancer: Comparison with EGFR-mutated lung cancer. Pathol Res Pract. 2019; 215(3):459-465 [PubMed] Related Publications
ALK-positive (ALK+) lung adenocarcinoma usually shows a more advanced-staged disease with frequent nodal metastasis and highly aggressive outcomes compared with EGFR-mutated lung cancers. The aim of this study was to investigate the expression profiles of several mucins in ALK + lung cancers to gain insight into the relationship between the more aggressive biological nature of ALK + lung cancers and the role of mucins. We examined the immunohistochemical profiles of mucins MUC1, MUC2, MUC5AC, and MUC6 in 19 ALK + lung cancers compared with 42 EGFR-mutated lung cancers. ALK + cancers were found to occur in younger patients and were characterized by a solid-predominant histologic subtype with frequent signet ring cells and peritumoral muciphages. By contrast, EGFR-mutated cancers lacked ALK-specific histological patterns. Although all MUC1 and MUC5AC were expressed in both subtypes, MUC1 expression in ALK + cancers was visualized exclusively through cytoplasmic staining, whereas those in EGFR-mutated cancers were predominantly membranous staining in apical area (92.9%) and focally in cytoplasmic staining (7.1%). MUC5AC expression in ALK + cancers was exclusively visualized through cytoplasmic staining (100%), whereas EGFR-mutated cancers showed predominantly perinuclear dot-like patterns (90.5%) and focal cytoplasmic staining (9.5%). MUC2 and MUC6 expression was not detected in either type of lung cancer. CONCLUSIONS: The high frequency of both MUC1 and MUC5AC cytoplasmic expression, coupled with a lack of MUC2 and MUC6 expression in ALK + lung cancer may contribute to the biologically aggressive behavior of ALK + cancer. Inhibitors to these types of mucins may thus act as a barrier to cancerous extension reducing their aggressive behavior.
BACKGROUND: Long non-coding RNAs (LncRNAs) emerging as pivotal marker in the procession of cancer, including colorectal cancer (CRC). Abnormal O-glycosylation is a crucial modification during cancer malignancy. The aim of this work is to analyze the alteration of O-glycosylation involved in CRC progression. METHODS: qRT-PCR is utilized to screen the differential linc01296 expression in CRC tissues and cell lines. Functionally, CRC cell proliferation, aggressiveness and apoptosis are measured through relevant experiments, including CCK8 assay, colony formation assay, transwell assay, western blot and flow cytometry. Dual-luciferase reporter gene assay and RIP assay confirm the direct interaction between linc01296 and miR-26a. The xenografts and liver metatstatic nude mice models are established to show the inner effect of linc01296. RESULTS: Differential expression of linc01296 is confirmed and closely correlated with the malignancy of CRC cell lines and poor clinical prognosis. Moreover, alteration of linc01296 affects CRC cell proliferation, metastasis and chemoresistance to 5-fluorouracil (5-FU) in vitro. Mechanically, linc01296 acts as a direct target of miR-26a, and thereby influenced CRC malignancy. Our investigation corroborates that linc01296 functions as an endogenous sponge of miR-26a to regulate mucin1 (MUC1) expression, catalyzed by GALNT3, which modulates the activity of PI3K/AKT pathway. Interestingly, upregulated linc01296 promotes the tumorigensis, liver metastasis and chemoresistance of CRC cell lines in vivo. CONCLUSION: These new findings indicate that linc01296/miR-26a/GALNT3 axis involves in the progression of CRC cells, illuminating the possible mechanism mediated by O-glycosylated MUC1 via PI3K/AKT pathway. This work renders potential diagnostic biomarkers and prospective therapeutic targets for CRC.
RATIONALE: For metastatic non-small cell lung cancer with no epidermal growth factor receptor mutations or anaplastic lymphoma kinase gene rearrangements, programmed cell death-1 (PD-1) blockade is preferentially recommended post first-line chemotherapy. However, still many patients do not respond to these agents. After development of resistance to PD-1 blockade, further evaluation of chemotherapy regimen will be necessary. PATIENT CONCERNS: A 57-year old man had cough with minimal whitish expectoration. Computed tomography (CT) scans showed that he had an upper lobe mass of his left lung and multiple lymphadenectasis, including mediastinal and hilar lymph nodes, and also to the right intrapulmonary lymph nodes. DIAGNOSES: The patient was diagnosed with adenocarcinoma after a biopsy was conducted on the upper lobe mass of his left lung. INTERVENTIONS: The patient received pemetrexed plus cisplatin (Pem-Cis) treatment for 6 cycles and sequential thoracic radiation as a therapeutic schedule. CT demonstrated a confirmed partial response after these treatments. Three months later, the tumors continued to grow. The patient received successive pemetrexed-based chemotherapy regimens; however, these regimens failed to stop tumor progression. The patient subsequently underwent 6 cycles of PD-1 mAb pembrolizumab treatment. OUTCOMES: Sensitivity of chemotherapy was restored, and the patient displayed a reduction in the size of enlarged mediastinal and hilar lymph nodes after 2 cycles of treatment with Pem-Cis, the initially used chemotherapy regimen. LESSONS: This outcome suggests that PD-1 blockade holds promise as a treatment strategy for reversion of chemotherapy resistance in refractory lung adenocarcinoma and warrants additional studies.
Bahreyni A, Alibolandi M, Ramezani M, et al. A novel MUC1 aptamer-modified PLGA-epirubicin-PβAE-antimir-21 nanocomplex platform for targeted co-delivery of anticancer agents in vitro and in vivo. Colloids Surf B Biointerfaces. 2019; 175:231-238 [PubMed] Related Publications
Conventional chemotherapy suffers from several drawbacks, including toxic side effects together with the development of resistance to the chemical agents. Therefore, exploring alternative therapeutic approaches as well as developing targeted delivery systems are in demand. Oligonucleotide-based therapy has emerged as a promising and alternative procedure for treating malignancies involving gene-related diseases. In the current study, a targeted delivery system was designed to target cancer cells based on two biocompatible polymers of poly (β amino ester) (PβAE) and poly (d, l-lactide-co-glycolide) (PLGA). In this system, antimir-21 as an inhibitor of microRNA-21 (miR-21) which is an oncomiR overexpressed in several human cancers was condensed with PβAE polymer and then PLGA was electrostatically deposited on this complex and provided a reservoir for positively charged drug, epirubicin (Epi). At the final stage, MUC1 aptamer as a targeting agent was covalently attached to the nanoparticles for selectively guided therapeutic delivery. The obtained results demonstrated that the fabricated MUC1 aptamer-modified nanocomplex could efficiently be internalized into MCF7 (human breast carcinoma cell) and C26 (murine colon carcinoma cell) cells through interaction between MUC1 aptamer and its receptor on the surfaces of these cell lines and decline cell viability in these cells but not in CHO cells (Chinese hamster ovary cell) as nontarget cells (MUC1 negative cells). The safety of PLGA-Epi-PβAE-antimir-21 nanocomplex and synergetic effect of Epi and antimir-21 in reducing cell viability of target cells were confirmed by treating MCF-7 and CHO cells with nanocomplex and MUC1 aptamer-modified nanocomplex. Moreover, it was demonstrated that MUC1 aptamer-modified nanocomplex could remarkably inhibit tumor growth in tumor-bearing mice compared with Epi alone.
Kawa MP, Baumert B, Litwińska Z, et al. Potential Leukemic Cells Engraftment After Hematopoietic Stem Cell Transplantation From Unrelated Donors With Undiagnosed Chronic Leukemia. Transplant Proc. 2018; 50(10):3789-3796 [PubMed] Related Publications
BACKGROUND: Donor-related neoplasms are a potential complication of treatment strategies involving stem cell transplantation. Although mechanisms for detection of short-term complications after these procedures are well developed, complications with delayed onset, notably transmission of chronic diseases such as chronic myeloid leukemia (CML), have been difficult to assess. Consequently, we studied the potential of human CML cells to engraft hematopoietic tissues after intravenous implantation in mice. METHODS: Human peripheral blood cells, collected from CML patients presenting with moderately increased white blood cells count before treatment, were transplanted into sub-lethally irradiated, immunodeficient mice. Five weeks after transplantation the nuclear cells were isolated from the murine bone marrow, spleen, and peripheral blood and were used to quantitatively detect human CD45 antigen by flow cytometry; qRT-PCR was used to detect the BCR-ABL1 fusion gene, and the human or murine beta-glucuronidase housekeeping gene was used to examine human-murine chimerism. RESULTS: We found that all evaluated animals had donor chimerism at the selected interval after transplant and the presence of a specific BCR-ABL1 fusion gene transcript was also detected. CONCLUSIONS: Our results suggest that the risk of neoplasm transmission cannot be eliminated during hematopoietic stem cell transplantation from undiagnosed CML donors with borderline leukocytosis. The obtained data confirms the potential of leukemic cells to viably engraft the hematopoietic organs post-transplantation in an immunosuppressed recipient.
Breast cancer is the most commonly diagnosed cancer in females; thus, there is an urgent requirement to identify precise biomarkers for the diagnosis and treatment of the disease. Mucin 1 (MUC1) is a glycoprotein that has been demonstrated to be involved in the metastasis and invasion of multiple tumor types. Bioinformatics analyses were conducted to indicate the prognostic value of MUC1 in breast cancer. Additionally, the expression level of MUC1 was assessed using Oncomine analysis. Furthermore, PrognoScan was used to analyze the prognostic value of MUC1 in breast cancer. Mutations of MUC1 were analyzed by the Catalogue of Somatic Mutations in Cancer and cBioPortal databases. In addition, University of California, Santa Cruz (UCSC) was used to examine the methylation status of MUC1. Co‑expression of MUC1 mRNA was detected with the cBioPortal, UCSC and Breast Cancer Gene‑Expression Miner v4.0 datasets. The results demonstrated that MCU1 is frequently overexpressed in breast cancer and is negatively associated with CpG sites. Furthermore, pooled data indicated that abnormally high expression of MUC1 indicates poor prognosis. Additionally, upregulation of MUC1 expression is associated with estrogen receptor‑ and progesterone receptor‑positive disease, aging and increased Scarff, Bloom and Richardson grade, but is not associated with triple‑negative and basal‑like status. Subsequent data mining across multiple large databases demonstrated a positive association between MUC1 mRNA expression and cyclic AMP‑responsive element‑binding protein 3‑like 4 (CREB3L4) in breast cancer tissues. The present data indicated that the overexpression of MUC1 indicates a poor prognosis in patients with breast cancer and is associated with MUC1 promoter methylation status. Additionally, MUC1 positively correlated with CREB3L4 and may serve as a potential prognostic factor and therapy target for breast cancer.
Mie M, Matsumoto R, Mashimo Y, et al. Development of drug-loaded protein nanoparticles displaying enzymatically-conjugated DNA aptamers for cancer cell targeting. Mol Biol Rep. 2019; 46(1):261-269 [PubMed] Related Publications
Modification of protein-based drug carriers with tumor-targeting properties is an important area of research in the field of anticancer drug delivery. To this end, we developed nanoparticles comprised of elastin-like polypeptides (ELPs) with fused poly-aspartic acid chains (ELP-D) displaying DNA aptamers. DNA aptamers were enzymatically conjugated to the surface of the nanoparticles via genetic incorporation of Gene A* protein into the sequence of the ELP-D fusion protein. Gene A* protein, derived from bacteriophage ϕX174, can form covalent complexes with single-stranded DNA via the latter's recognition sequence. Gene A* protein-displaying nanoparticles exhibited the ability to deliver the anticancer drug paclitaxel (PTX), whilst retaining activity of the conjugated Gene A* protein. PTX-loaded protein nanoparticles displaying DNA aptamers known to bind to the MUC1 tumor marker resulted in increased cytotoxicity with MCF-7 breast cancer cells compared to PTX-loaded protein nanoparticles without the DNA aptamer modification.
Endo S, Nishimura N, Kawano Y, et al. MUC1/KL-6 expression confers an aggressive phenotype upon myeloma cells. Biochem Biophys Res Commun. 2018; 507(1-4):246-252 [PubMed] Related Publications
The sialic glycoprotein, MUC1, is known to be involved in the pathogenesis of various types of cancers. KL-6 is one of the surface antigens of MUC1 and also a marker of interstitial pneumonitis. A fraction of patients with myeloma (3.9%) have elevated serum KL-6 levels without any evidence of interstitial pneumonitis and their myeloma cells have high MUC1 expression. We established a myeloma cell line designated EMM1 from a patient with multiple myeloma accompanied with elevated serum KL-6. EMM1 cells expressed high levels of MUC1 compared with other myeloma cell lines. Knockdown of MUC1 in EMM1 cells induced cell cycle arrest during S phase and apoptosis, suggesting that the MUC1 expression is involved in accelerated growth of EMM1 cells. RNA-seq analysis suggests that MUC1 expression activates k-ras and TNFα-induced NFκB pathways in EMM1 cells. We injected EMM1 cells subcutaneously into Rag2
Zeinali T, Mansoori B, Mohammadi A, Baradaran B Regulatory mechanisms of miR-145 expression and the importance of its function in cancer metastasis. Biomed Pharmacother. 2019; 109:195-207 [PubMed] Related Publications
MicroRNAs are post-transcriptional mediators of gene expression and regulation, which play influential roles in tumorigenesis and cancer metastasis. The expression of tumor suppressor miR-145 is reduced in various cancer cell lines, containing both solid tumors and blood malignancies. However, the responsible mechanisms of its down-regulation are a complicated network. miR-145 is potentially able to inhbit tumor cell metastasis by targeting of multiple oncogenes, including MUC1, FSCN1, Vimentin, Cadherin, Fibronectin, Metadherin, GOLM1, ARF6, SMAD3, MMP11, Snail1, ZEB1/2, HIF-1α and Rock-1. This distinctive role of miR-145 in the regulation of metastasis-related gene expression may introduce miR-145 as an ideal candidate for controlling of cancer metastasis by miRNA replacement therapy. The present review aims to discuss the current understanding of the different aspects of molecular mechanisms of miR-145 regulation as well as its role in r metastasis regulation.
Dorokhov YL, Sheshukova EV, Bialik TE, Komarova TV Human Endogenous Formaldehyde as an Anticancer Metabolite: Its Oxidation Downregulation May Be a Means of Improving Therapy. Bioessays. 2018; 40(12):e1800136 [PubMed] Related Publications
Malignant cells are characterized by an increased content of endogenous formaldehyde formed as a by-product of biosynthetic processes. Accumulation of formaldehyde in cancer cells is combined with activation of the processes of cellular formaldehyde clearance. These mechanisms include increased ALDH and suppressed ADH5/FDH activity, which oncologists consider poor and favorable prognostic markers, respectively. Here, the sources and regulation of formaldehyde metabolism in cancer cells are reviewed. The authors also analyze the participation of oncoproteins such as fibulins, FGFR1, HER2/neu, FBI-1, and MUC1-C in the control of genes related to formaldehyde metabolism, suggesting the existence of two mutually exclusive processes in cancer cells: 1) production and 2) oxidation and elimination of formaldehyde from the cell. The authors hypothesize that the study of the anticancer properties of disulfiram and alpha lipoic acid - which affect the balance of formaldehyde in the body - may serve as the basis of future anticancer therapy.
Jester R, Znoyko I, Garnovskaya M, et al. Expression of renal cell markers and detection of 3p loss links endolymphatic sac tumor to renal cell carcinoma and warrants careful evaluation to avoid diagnostic pitfalls. Acta Neuropathol Commun. 2018; 6(1):107 [PubMed] Free Access to Full ArticleRelated Publications
Endolymphatic sac tumor (ELST) is a rare neoplasm arising in the temporal petrous region thought to originate from endolymphatic sac epithelium. It may arise sporadically or in association with Von-Hippel-Lindau syndrome (VHL). The ELST prevalence in VHL ranges from 3 to 16% and may be the initial presentation of the disease. Onset is usually in the 3rd to 5th decade with hearing loss and an indolent course. ELSTs present as locally destructive lesions with characteristic computed tomography imaging features. Histologically, they show papillary, cystic or glandular architectures. Immunohistochemically, they express keratin, EMA, and variably S100 and GFAP. Currently it is recommended that, given its rarity, ELST needs to be differentiated from other entities with similar morphologic patterns, particularly other VHL-associated neoplasms such as metastatic clear cell renal cell carcinoma (ccRCC). Nineteen ELST cases were studied. Immunohistochemistry (18/19) and single nucleotide polymorphism microarray testing was performed (12/19). Comparison with the immunophenotype and copy number profile in RCC is discussed. Patients presented with characteristic bone destructive lesions in the petrous temporal bones. Pathology of tumors showed characteristic ELST morphology with immunoexpression of CK7, GFAP, S100, PAX-8, PAX-2, CA-9 in the tumor cells. Immunostaines for RCC, CD10, CK20, chromogranin A, synaptophysin, TTF-1, thyroglobulin, and transthyretin were negative in the tumor cells. Molecular testing showed loss of 3p and 9q in 66% (8/12) and 58% (7/12) cases, respectively. Immunoreactivity for renal markers in ELST is an important diagnostic caveat and has not been previously reported. In fact, renal markers are currently recommended in order to rule out metastatic RCC although PAX gene complex and CA-9 have been implicated in the development of the inner ear. Importantly copy number assessment of ELST has not been previously reported. Loss of 3p (including the VHL locus) in ELST suggests similar mechanistic origins as ccRCC.
Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of
The association of BRCA1/2 mutations with melanoma is not completely determined; the interpretation of variants of unknown significance is also problematic. To evaluate these issues we explored the molecular basis of melanoma risk by performing whole-exome sequencing on a cohort of 96 unrelated Polish early-onset melanoma patients and targeted sequencing of BRCA1/2 genes on additional 30 melanoma patients with familial aggregation of breast and other cancers. Sequencing was performed on peripheral blood. We evaluated MutationTaster, Polyphen2, SIFT, PROVEAN algorithms, analyzed segregation with cancer disease (in both families with identified BRCA2 variants) and in one family performed LOH (based on 2 primary tumors). We found neither pathogenic mutations nor variants of unknown significance within BRCA1. We identified two BRCA2 variants of unknown significance: c.9334G>A and c.4534 C>T. Disease allele frequency was evaluated by genotyping of 1230 consecutive melanoma cases, 5000 breast cancer patients, 3500 prostate cancers and 9900 controls. Both variants were found to be absent among unselected cancer patients and healthy controls. The MutationTaster, Polyphen2 and SIFT algorithms indicate that c.9334G>A is a damaging variant. Due to lack of tumour tissue LOH analysis could not be performed for this variant. The variant segregated with the disease. The c.4534 C>T variant did not segregate with disease, there was no LOH of the variant. The c.9334G>A variant, classified as a rare variant of unknown significance, on current evidence may predisposes to cancers of the breast, prostate and melanoma. Functional studies to describe how the DNA change affects the protein function and a large multi-center study to evaluate its penetrance are required.
Bartholomew AJ, Dohnalek H, Prins PA, et al. Underuse of exon mutational analysis for gastrointestinal stromal tumors. J Surg Res. 2018; 231:43-48 [PubMed] Related Publications
BACKGROUND: Tyrosine kinase inhibitors (TKI) have become the guideline-recommended therapy for high-risk resected and advanced gastrointestinal stromal tumors (GISTs). Exon mutational analysis (EMA) is used to inform pretherapy response to TKI and may predict overall prognosis. Despite these benefits, EMA remains underused, and its impact on TKI therapy decision-making remains unexplored. MATERIALS AND METHODS: A retrospective cohort was established from 104 patients receiving treatment for GISTs from 2006 to 2017. Current National Comprehensive Cancer Network guidelines indicate that EMA should be considered for all patients undergoing TKI therapy to identify genotypes that are likely, or unlikely, to respond to treatment. We first tracked guideline-considered EMA use and subsequent impact on treatment decision-making. A questionnaire was then administered to gastrointestinal medical oncologists to assess EMA perception. RESULTS: Among 104 GIST patients, 54 (52%) received TKI therapy. Of these, only 22 (41%) received EMA. Informed by EMA, treatment decisions included 59% who continued with original TKI therapy, 32% who switched to an alternative TKI, and 9% who discontinued or received no TKI. Although 92% of physicians indicated EMA was a valuable tool, only 62% indicated they used it "frequently" or "always" to inform treatment decisions. CONCLUSIONS: Less than half of patients receiving TKI therapy for GISTs received EMA at a comprehensive cancer center. Despite this low uptake, when it was performed, EMA guided alternative treatment decision in 41% of patients. Physician survey responses indicated that interventions targeting physician education and an electronic medical record reminder may improve EMA uptake.
Wiktorowicz M, Mlynarski D, Pach R, et al. Rationale and feasibility of mucin expression profiling by qRT-PCR as diagnostic biomarkers in cytology specimens of pancreatic cancer. Pancreatology. 2018; 18(8):977-982 [PubMed] Related Publications
BACKGROUND: Aberrantly expressed mucin glycoproteins (MUC) play important roles in pancreatic ductal adenocarcinoma (PDAC), yet their use as a diagnostic aid in fine-needle aspiration biopsy (FNAB) is poorly documented. The aim of this study was to investigate the rationale and feasibility of mucin (MUC1, MUC2, MUC3, MUC4, MUC5AC, and MUC6) expression profiling by RT-PCR for diagnostic applications in cytology. METHODS: Mucin expression was examined by RT-PCR and immunohistochemistry in specimens resected from patients with pancreatic (n = 101), ampullary (n = 23), and common bile duct (n = 10) cancers and 33 with chronic pancreatitis. Furthermore, mucin profiling by RT-PCR was prospectively compared in surgical and biopsy specimens of 40 patients with pancreatic solid tumours qualified for FNAB prior to surgery. RESULTS: A logistic regression model to distinguish PDAC from chronic pancreatitis using RT-PCR profiling included MUC3, MUC5AC, and MUC6. The same set of mucins differentiated ampullary and bile duct cancers from chronic pancreatitis. AUCs for the ROC curves derived from the two models were 0.95 (95%CI 0.87-0.99) and 0.92 (95%CI 0.81-0.98), respectively. The corresponding positive likelihood ratios were 6.02 and 5.97, while the negative likelihood ratios were 0.10 and 0.12. AUCs of ROC curves obtained by RT-PCR and immunohistochemistry demonstrated that both analytical methods were comparable. Surgical and cytological samples showed significantly correlated values of ΔCt for individual mucins with the overall Pearson's correlation coefficient r = 0.841 (P = 0.001). CONCLUSIONS: Mucin expression profiling of pancreatic cancer with RT-PCR is feasible and may be a valuable help in discriminating malignant lesions from chronic pancreatitis in FNAB cytology.
Liang X, Li Z, Men Q, et al. miR-326 functions as a tumor suppressor in human prostatic carcinoma by targeting Mucin1. Biomed Pharmacother. 2018; 108:574-583 [PubMed] Related Publications
Accumulating evidence suggests that microRNA-326 (miR-326) serves as a tumor suppressor in the initiation and progression of several human malignancies. However, the biological function and underlying molecular mechanism of miR-326 in prostatic carcinoma (PCa) remains largely unknown. In the present study, we found that miR-326 expression level was significantly downregulated in both primary PCa and castration-resistant PCa (CRPC) tissue samples as detected by qRT-PCR. Downregulation of miR-326 was closely associated with aggressive progression and poor prognosis of primary PCa patients. Gain- and lose- functional experiments revealed that forced expression of miR-326 significantly inhibited cell proliferation, colony formation, migration and invasion, induced G0/G1 cell cycle arrest, and promoted apoptosis in PCa cells in vitro, whereas, knockdown of miR-326 expression showed the opposite results. Overexpression of miR-326 also suppressed tumor growth in xenografted nude mice in vivo. Moreover, Luciferase reporter, qRT-PCR, and western blot assays identified that the 3'-untranslated region (3'-UTR) of Mucin1 (MUC1) was a direct target region of miR-326. Spearman's correlation analysis also confirmed an inverse relationship between miR-326 and MUC1 expressions in primary PCa tissue samples. In addition, restoration of MUC1 expression effectively abrogated the inhibitory effects of miR-326 on PCa proliferation, invasion and migration through the activation of JNK signaling pathway. Therefore, these data indicated that miR-326 functioned as a tumor suppressor in PCa by negatively regulating MUC1, and that miR-326 might serve as a potential therapeutic candidate for PCa treatment.
Kurihara J, Yokoo S, Ichikawa M, et al. Intraosseous intraneural perineurioma derived from the inferior alveolar nerve with an abnormality of chromosome 22 and expression of the BCR-ABL fusion gene: report of a case and review of recent literature. World J Surg Oncol. 2018; 16(1):189 [PubMed] Free Access to Full ArticleRelated Publications
BACKGROUND: Perineurioma (PN) is a peripheral nerve disease that primarily develops in the limbs and trunk and very rarely occurs in the oral cavity. PN is classified into two types: intraneural perineurioma (INPN) and soft tissue perineurioma (extraneural perineurioma, ENPN). In this article, we report a patient with mandibular body INPN derived from the perineurium of the inferior alveolar nerve. CASE PRESENTATION: The patient was a 43-year-old male. He consulted our department for a detailed examination of the right mandibular body. A biopsy was performed at another hospital and he was diagnosed with a schwannoma. At his first visit, hypesthesia extending from the right lower lip to the mental region was recognized and enlargement of the right mandibular canal was confirmed with X-ray CT and MRI. Considering the possibility of future tumor growth, we extirpated the tumor under general anesthesia. Cystic tumor was seen continuously in the inferior alveolar nerve. Immunohistologically, the tumor cells were positive for Glut-1, weakly positive for EMA, and weakly positive for Claudin-1, and the histopathological diagnosis was INPN. In addition, absence of the BCR region of chromosome 22 and expression of the BCR-ABL fusion gene were observed by fluorescent in situ hybridization (FISH), and a chromosome 22 abnormality was confirmed. These findings indicated that the disease was a neoplastic lesion. CONCLUSION: Expression of the BCR-ABL fusion gene in INPN that develops in the oral cavity is thought to be very rare, and to the best of our knowledge, ours is the first case to be reported in the literature. About three postoperative years have passed, but findings suggestive of recurrence have not been observed.
RATIONALE: Primary poorly differentiated lacrimal gland adenocarcinoma in the orbital region is an extremely rare type of neoplasm with only 1 related case in the literature. Its high grade of malignancy makes the timely data reported necessary. Hence, we present an extremely rare disease with biopsy results and recommendations on clinical treatment in an elderly male with Chinese descent. PATIENT CONCERNS: A 66-year-old Chinese man presented with swelling in the left ocular region and eyeball proptosis. On physical examination, the patient had redness, tenderness, and swelling of the left eye. A surgical incision was noted on the left orbital region. Left eye movements were restricted. DIAGNOSES: Immunohistochemical examination revealed pan-cytokeratin (PCK, +), p63 (partial, +), cytokeratin 7 (CK7, +), cytokeratin 14 (CK14, +), epithelial membrane antigen (EMA, +), protein expressed by erythroblast transformation-specific related gene (ERG, -), S-100 (, -), Epstein-Barr virus-encoded small RNA (EBER, -), smooth muscle actin (SMA, -), and Ki-67 (with a proliferation index approximately 40%). After carefully reviewed the manifestations, imaging findings, and immunohistochemical evidences, a diagnosis of poorly differentiated adenocarcinoma of lacrimal gland was made. INTERVENTION: Based on the gene sequencing results, we started the patient with an intensive PF chemotherapy including a combination of cisplatine, fluorouracil, and epirubicin. Two months later, radiotherapy was introduced to the therapy regimen. OUTCOMES: The patient responded well to the treatment without severe adverse events. MRI scan showed remarkable remission. LESSONS: This rare case report will help raise the awareness of high grade lacrimal gland cancer, and subsequently aid the diagnosis in future cases. Positive immunohistochemical markers of CK7, CK14, EMA, p63, and high proliferation index of Ki-67 can help establishing a diagnosis, and cisplatine-fluorouracil program is proved feasible. We share the difficulties we have encountered, hoping to improve patient care in the future.
Cao Z, Hao Z, Xin M, et al. Endogenous and exogenous galectin-3 promote the adhesion of tumor cells with low expression of MUC1 to HUVECs through upregulation of N-cadherin and CD44. Lab Invest. 2018; 98(12):1642-1656 [PubMed] Related Publications
Tumor cell-endothelial adhesion is one of the key steps in tumor cell haematogenous dissemination in metastasis and was previously shown to be mediated by interaction of galectin-3 with the transmembrane mucin protein MUC1. In this study, the effect of exogenous as well as endogenous galectin-3 on adhesion of two cell lines (low MUC1-expressing human prostate cancer PC-3M cells and non-small-cell lung cancer A549 cells) to monolayer of umbilical vein endothelial cells (HUVECs) was investigated. We found that suppression of endogenous galectin-3 expression reduced tumor cell adhesion to HUVECs and also decreased cell invasion and migration. Exogenous galectin-3 promoted tumor cell adhesion to HUVECs by entering cells. Both exogenous and endogenous galectin-3 upregulated the expression of β-catenin and increased β-catenin nuclear accumulation, and subsequently upregulated the expression of N-cadherin and CD44. We deduced that both exogenous as well as endogenous galectin-3 promoted low MUC1-expressing cancer cell adhesion to HUVECs by increasing the expression of N-cadherin and CD44 via an increase of nuclear β-catenin accumulation. These results were confirmed further by using a β-catenin/TCF transcriptional activity inhibitor, N-cadherin or CD44 siRNAs. Taken together, our results suggest a new molecular mechanism of galectin-3-mediated cell adhesion in cancer metastasis.
Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the
BACKGROUND: Breast cancer is one of the most prevalent types of cancer and a leading cause of death in women. MATERIALS AND METHODS: An experimental model of breast cancer was induced in female albino rats using single intragastric dose of 7, 12 dimethylbenz (α) anthracene (DMBA) in sesame oil (50 mg/kg b.wt). Four months after DMBA administration, incidence of breast cancer was confirmed by measuring cancer antigen 15-3 (CA15-3) serum levels. RESULTS: Level of CA15-3 was normalized in DMBA group administered TOE for 4 weeks. Administration of DMBA increased expression of
Malignant glioma is a brain tumor with a very high mortality rate resulting from the specific morphology of its infiltrative growth and poor early detection rates. The causes of one of its very specific types, i.e., post-traumatic glioma, have been discussed for many years, with some studies providing evidence for mechanisms where the reaction to an injury may in some cases lead to the onset of carcinogenesis in the brain. In this review of the available literature, we discuss the consequences of breaking the blood⁻brain barrier and consequences of the influx of immune-system cells to the site of injury. We also analyze the influence of inflammatory mediators on the expression of genes controlling the process of apoptosis and the effect of chemical mutagenic factors on glial cells in the brain. We present the results of experimental studies indicating a relationship between injury and glioma development. However, epidemiological studies on post-traumatic glioma, of which only a few confirm the conclusions of experimental research, indicate that any potential relationship between injury and glioma, if any, is indirect.
BACKGROUND: The Tn neoantigen (GalNAcα1-O-Ser/Thr) is an O-glycan expressed in various types of human cancers. Studies in several Tn-expressing cancer cell lines and pancreatic tumors have identified loss of Cosmc expression caused by either mutations or promoter hypermethylation. In this study, we explored the mechanism(s) for Tn expression in human colorectal cancers (CRC). METHODS: Tn-expressing cell populations were isolated from CRC cell lines by Fluorescence-associated cell sorting (FACS). The expression of the Tn and sialylated Tn (STn) antigens, Cosmc, T-synthase, and mucins was characterized in paired specimens with CRC and in CRC cell lines by immunostaining, western blot, and qPCR. RESULTS: Using well-defined monoclonal antibodies, we confirmed prevalent Tn/STn expression in CRC samples. However, a majority of these tumors had elevated T-synthase activity and expression of both Cosmc and T-synthase proteins. Meanwhile, Tn antigen expression was not caused by mucin overproduction. In addition, we found that Tn-expressing CRC cell lines had either loss-of-function mutations in Cosmc or reversible Tn antigen expression, which was not caused by the deficiency of T-synthase activity. CONCLUSIONS: Our results demonstrate multiple mechanisms for Tn expression in CRCs.
Deng M, Jing DD, Meng XJ Effect of MUC1 siRNA on drug resistance of gastric cancer cells to trastuzumab. Asian Pac J Cancer Prev. 2013; 14(1):127-31 [PubMed] Related Publications
Trastuzumab is the first molecular targeting drug to increase the overall survival rate in advanced gastric cancer. However, it has also been found that a high intrinsic or primary trastuzumab resistance exists in some proportion of gastric cancer patients. In order to explore the mechanism of resistance to trastuzumab, firstly we investigated the expression of MUC1 (membrane-type mucin 1) in gastric cancer cells and its relationship with drug-resistance. Then using gene-silencing, we transfected a siRNA of MUC1 into drug-resistant cells. The results showed the MKN45 gastric cell line to be resistant to trastuzumab, mRNA and protein expression of MUC1 being significantly upregulated. After transfection of MUC1 siRNA, protein expression of MUC1 in MKN45cells was significantly reduced. Compared with the junk transfection and blank control groups, the sensitivity to trastuzumab under MUC1 siRNA conditions was significantly increased. These results imply that HER2-positive gastric cancer cell MKN45 is resistant to trastuzumab and this resistance can be cancelled by silencing expression of the MUC1 gene.
Dai F, Zhang Y, Zhu X, et al. The anti-chemoresistant effect and mechanism of MUC1 aptamer-miR-29b chimera in ovarian cancer. Gynecol Oncol. 2013; 131(2):451-9 [PubMed] Related Publications
OBJECTIVE: Currently, there are no effective therapies for advanced ovarian cancer. In this study, we aim to determine the anti-tumor effect of MUC1 aptamer-miR-29b chimera in xenograft ovarian cancer models and chemo-resistance tumor model and to further explore the associated mechanism. METHODS: Xenograft ovarian cancer animal models were established using OVCAR-3, OVCA420, and OVCAR-3-Taxol cancer cells. The chimera (Chi-29b) was delivered through intraperitoneal injections. Tumor growth was evaluated. Gene expression and PTEN methylation were measured. RESULTS: We demonstrated that intratumoral injection of Chi-29b chimera significantly inhibited the growth of xenograft OVCAR-3 tumors through downregulating PTEN methylation, subsequent PTEN expression, as well as downregulating MAPK 4 and IGF1 expressions. In contrast, Chi-29b inhibited tumor growth in OVCA420 tumors by downregulating MAPK 4 & 10 and IGF1 expression without affecting PTEN expression. Intraperitoneal injection of Chi-29b significantly increased apoptosis in paclitaxel-resistant OVCAR-3 cells and inhibited the growth of xenograft OVCAR-3-Taxol tumors. The anti-chemoresistant role of Chi-29b in OVCAR-3-Taxol tumors was associated with the activation of PTEN signaling and downregulation of MAPK 4 and 10 and IGF1 expression. CONCLUSION: Our study indicated that Chi-29b chimera can effectively exert an anti-tumor effect in xenograft tumor models and an anti-chemoresistant role through inhibiting cancer stem cell activation.
MUC1 glycoprotein is often found overexpressed and hypoglycosylated in tumor cells from numerous cancer types. Since its discovery MUC1 has been an attractive target for antitumor immunotherapy. Indeed, in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 in an HLA-restricted and HLA-unrestricted manner, although some animal models have highlighted the possible development of tolerogenic responses against this antigen. These observations permit the development of new T-cell vaccine strategies capable of inducing an MUC1-specific cytotoxic T cell response in cancer patients. Some of these strategies are now being tested in clinical trials against different types of cancer. To date, encouraging clinical responses have been observed with some MUC1 vaccines in phase II/III clinical trials. This paper compiles knowledge regarding MUC1 as a promising tumor antigen for antitumor therapeutic vaccines applicable to numerous cancers. We also summarize the results of MUC1-vaccine-based clinical trials.
Sinn BV, von Minckwitz G, Denkert C, et al. Evaluation of Mucin-1 protein and mRNA expression as prognostic and predictive markers after neoadjuvant chemotherapy for breast cancer. Ann Oncol. 2013; 24(9):2316-24 [PubMed] Related Publications
BACKGROUND: Mucin-1 (MUC1) is a promising antigen for the development of tumor vaccines. We evaluated the frequency of MUC1 expression and its impact on therapy response and survival after neoadjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: Pre-treatment core biopsies of patients from the GeparTrio neoadjuvant trial (NCT 00544765) were evaluated for MUC1 by immunohistochemistry (IHC; N = 691) and quantitative RT-PCR (qRT-PCR; N = 286) from formalin-fixed paraffin-embedded (FFPE) samples. RESULTS: MUC1 protein and mRNA was detectable in the majority of cases and was associated with hormone-receptor-positive status (P < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (P = 0.017 and P < 0.001) and with longer patient survival (P = 0.03 and P < 0.001). In multivariable analysis, MUC1 protein and mRNA expression were independently predictive (P = 0.001 and P < 0.001). MUC1 protein and mRNA expression were independently prognostic for overall survival (P = 0.029 and P = 0.015). CONCLUSIONS: MUC1 is frequently expressed in breast cancer and detectable on mRNA and protein level from FFPE tissue. It provides independent predictive information for therapy response and survival after neoadjuvant chemotherapy. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker.
MUC1 (CD227), a membrane tethered mucin glycoprotein, is overexpressed in >60% of human pancreatic cancers (PCs), and is associated with poor prognosis, enhanced metastasis and chemoresistance. The objective of this study was to delineate the mechanism by which MUC1 induces drug resistance in human (BxPC3 and Capan-1) and mouse (KCKO, KCM) PC cells. We report that PC cells that express high levels of MUC1 exhibit increased resistance to chemotherapeutic drugs (gemcitabine and etoposide) in comparison with cells that express low levels of MUC1. This chemo resistance was attributed to the enhanced expression of multidrug resistance (MDR) genes including ABCC1, ABCC3, ABCC5 and ABCB1. In particular, levels of MRP1 protein encoded by the ABCC1 gene were significantly higher in the MUC1-high PC cells. In BxPC3 and Capan-1 cells MUC1 upregulates MRP1 via an Akt-dependent pathway, whereas in KCM cells MUC1-mediated MRP1 upregulation is via an Akt-independent mechanism. In KCM, BxPC3 and Capan-1 cells, the cytoplasmic tail motif of MUC1 associates directly with the promoter region of the Abcc1/ABCC1 gene, indicating a possible role of MUC1 acting as a transcriptional regulator of this gene. This is the first report to show that MUC1 can directly regulate the expression of MDR genes in PC cells, and thus confer drug resistance.
Core 2 β-1,6-N-acetylglucosaminyltransferase (C2GnT) forms an N-acetylglucosamine branch in O-glycans (core 2 O-glycans) of cell surface glycoproteins. C2GnT-expressing bladder tumors acquire highly metastatic phenotypes by surviving longer in host blood circulation. However, the detailed mechanisms underlying this increased survival remain unclear. In this study, we report that the expression of C2GnT in bladder tumors positively correlates with tumor progression and that bladder tumor cell-surface mucin 1 (MUC1) carrying core 2 O-glycans plays an important role in the evasion from natural killer (NK) cell attack. In C2GnT-expressing bladder tumor cells, heavily core 2 O-glycosylated MUC1 carries poly-N-acetyllactosamine in its O-glycans and galectin-3 binds to MUC1 through this poly-N-acetyllactosamine. The binding of galectin-3 to poly-N-acetyllactosamine in MUC1 core 2 O-glycans attenuates the interaction of the tumor cells with NK cells and interferes with the access of tumor necrosis factor-related apoptosis-inducing ligand to the tumor cell surface. These effects of MUC1 carrying core 2 O-glycans on NK cell attack facilitate C2GnT-expressing tumor cells to evade NK cell immunity and survive longer in host blood circulation. We reveal that MUC1 carrying core 2 O-glycans thus functions as a molecular shield against NK cell attack, thereby promoting bladder tumor metastasis.
Swallow DM, Gendler S, Griffiths B, et al. The human tumour-associated epithelial mucins are coded by an expressed hypervariable gene locus PUM. Nature. 1987 Jul 2-8; 328(6125):82-4 [PubMed] Related Publications
A single highly-polymorphic autosomal gene locus PUM codes for a family of mucin-type glycoproteins, separable by SDS-gel electrophoresis, which we first identified in human urine. The locus also codes for glycoproteins which are abundant in several other normal epithelial tissues and body fluids, including milk, and in tumours of epithelial origin. These mucin-type glycoproteins seem to be very immunogenic in rodents and, in a search for epithelial specific or tumour-associated antigens, a large number of related antibodies have been isolated which bind to the PUM-coded mucins. Many of the antibodies show a pronounced tumour specificity on immunohistology and are being used widely in cancer diagnosis in vitro and in vivo and even in cancer therapy. To investigate the expression of these antigens in normal and malignant cells complementary DNA coding for the mammary mucin has been isolated. Here we present evidence obtained using this cDNA that the PUM locus is a hypervariable 'minisatellite' region of human DNA similar to those described by several groups, but which is novel in that it is transcribed and translated, and that the same polymorphism is demonstrable in the expressed gene product.
Gendler SJ, Lancaster CA, Taylor-Papadimitriou J, et al. Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin. J Biol Chem. 1990; 265(25):15286-93 [PubMed] Related Publications
Human mammary cells present on the cell surface a polymorphic epithelial mucin (PEM) which is developmentally regulated and aberrantly expressed in tumors. PEM carries tumor-associated epitopes recognized by the monoclonal antibodies HMFG-1, HMFG-2, and SM-3. Previously isolated partial cDNA clones revealed that the core protein contained a large domain consisting of variable numbers of 20-amino acid repeat units. We now report the full sequence for PEM, as deduced from cDNA sequences. The encoded protein consists of three distinct regions: the amino terminus consisting of a putative signal peptide and degenerate repeats; the major portion of the protein which is the tandem repeat region; the carboxyl terminus consisting of degenerate tandem repeats and a unique sequence containing a transmembrane sequence and a cytoplasmic tail. Potential O-glycosylation sites (serines or threonines) make up more than one-fourth of the amino acids. Length variations in the tandem repeat result in PEM being an expressed variable number tandem repeat locus. Tandem repeats appear to be a general characteristic of mucin core proteins.
Hirasawa Y, Kohno N, Yokoyama A, et al. Natural autoantibody to MUC1 is a prognostic indicator for non-small cell lung cancer. Am J Respir Crit Care Med. 2000; 161(2 Pt 1):589-94 [PubMed] Related Publications
A great deal of attention has been focused on the antitumor effects of anti-MUC1 humoral and cellular responses. We examined whether anti-MUC1 antibody is present in patients with lung cancer, and evaluated its prognostic value. Serum was obtained from 30 patients with nonresectable, non-small cell lung cancer (NSCLC) and 60 healthy volunteers. The presence of anti-MUC1 antibody was determined by enzyme-linked immunosorbent assay. The patients were observed for a median follow-up time of 54.0 mo. Overall survival was estimated by the Kaplan-Meier method. Multivariate analyses were performed using the Cox proportional hazards regression model. Anti-KL-6/MUC1 antibody levels of the patients were significantly lower than those of normal individuals (p < 0.001). One-year survival rate of patients with high concentrations of anti-KL-6/MUC1 antibody was significantly higher than that of patients with low levels of anti-KL-6/MUC1 antibody (90.9% versus 21.1%, p < 0.001). Anti-KL-6/MUC1 antibody status was most strongly correlated with mortality, followed by lymph node status and albumin levels, whereas sex, serum lactate dehydrogenase (LDH), and carcinoembryonic antigen (CEA) levels, and metastasis status did not correlate with mortality. These preliminary results indicate that the degree of decrease in antibody level may be associated with a patient's prognosis.
Situ D, Wang J, Ma Y, et al. Expression and prognostic relevance of MUC1 in stage IB non-small cell lung cancer. Med Oncol. 2011; 28 Suppl 1:S596-604 [PubMed] Related Publications
The goal of this study was to evaluate the expression of MUC1 in stage IB non-small cell lung cancer (NSCLC) and its prognostic significance. The expression of MUC1 in 178 NSCLC specimens was evaluated via immunohistochemistry. A reproducible semiquantitative method which took both staining percentage and intensity into account was applied for immunohistochemical scoring, and receiver operating characteristic curve analysis was utilized to select the cut-off score for high or low MUC1 expression. Then, the correlations between MUC1 expression and clinicopathological features and its prognostic relevance were determined. In this study, high MUC1 expression was detected more frequently in adenocarcinomas (86.3%) and other NSCLCs (74.1%) than in squamous cell carcinomas (39.1%, P < 0.001). The Kaplan-Meier survival curves showed that up-regulated expression of MUC1 indicated poorer overall survival (OS) and disease-free survival (DFS) (P = 0.011 and P = 0.008, respectively), especially for those with non-squamous cell carcinomas (P = 0.033 and P = 0.011, respectively). Multivariate analysis also confirmed that MUC1 expression was an independent prognostic factor for both OS and DFS in stage IB NSCLC (P = 0.008 and P = 0.004, respectively). MUC1 might be correlated with the histogenesis of lung adenocarcinoma, and its elevated expression may be an adverse prognostic indicator for the patients with stages IB NSCLC, particularly for those with non-squamous cell carcinomas.
Wei X, Xu H, Kufe D Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005; 7(2):167-78 [PubMed] Related Publications
The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas. The present work demonstrates that MUC1 associates with the p53 tumor suppressor, and that this interaction is increased by genotoxic stress. The MUC1 cytoplasmic domain binds directly to p53 regulatory domain. Chromatin immunoprecipitation assays demonstrate that MUC1 coprecipitates with p53 on the p53-responsive elements of the p21 gene promoter and coactivates p21 gene transcription. Conversely, MUC1 attenuates activation of Bax transcription. In concert with these results, MUC1 promotes selection of the p53-dependent growth arrest response and suppresses the p53-dependent apoptotic response to DNA damage. These findings indicate that MUC1 regulates p53-responsive genes and thereby cell fate in the genotoxic stress response.
Schroeder JA, Adriance MC, Thompson MC, et al. MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion. Oncogene. 2003; 22(9):1324-32 [PubMed] Related Publications
MUC1 is aberrantly expressed in greater than 90% of all breast carcinomas, yet its function as a tumor antigen is not fully understood. Recently, studies have shown that MUC1 interacts with beta-catenin, erbB receptors, src, GSK-3beta and protein kinase Cdelta, possibly in a complex that promotes the disassembly of adherens junctions and the invasion of cells. Here we show that the deletion of Muc1 expression from MMTV-Wnt-1 transgenic mice results in a significant increase in the time to mammary gland tumor onset. Analysis of MMTV-Wnt-1 tumors on a wild-type Muc1 background shows a tumor-specific complex formation between Muc1 and beta-catenin that can be observed in both the membrane and the cytoplasm of transformed epithelium. Analysis of primary human adenocarcinomas revealed that this MUC1/beta-catenin interaction occurs in both primary and metastatic tumors, but is dramatically increased in metastatic lesions. Addition of MUC1-cytoplasmic domain peptides to the invasive MDA-MB-468 and MDA-MB-231 cell lines increases their invasive capability, and these peptides colocalize with both beta-catenin and the focal adhesion protein vinculin, primarily at sites of membrane invasion into a collagen matrix. These data indicate a potential mechanism for MUC1 promotion of invasive tumorigenesis in the breast through the modulation of beta-catenin localization and subsequent cytoskeletal dynamics.
Dyomin VG, Palanisamy N, Lloyd KO, et al. MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets. Blood. 2000; 95(8):2666-71 [PubMed] Related Publications
The band 1q21 is among the most common sites affected by chromosomal translocations in lymphoid, myeloid, epithelial, and sarcomatous lesions. In non-Hodgkin's lymphoma (NHL), translocations and duplications affecting this chromosomal site are frequently, but not exclusively, seen in association with primary abnormalities such as the t(14;18)(q32;q21) and t(8;14)(q24;q32) translocations, suggesting a role for 1q21 rearrangements in tumor progression. We report here the characterization and cloning of breakpoints in a case of extranodal ascitic B-cell lymphoma with a t(1;14)(q21;q32) translocation. The breakpoints on the der(1) and der(14) chromosomes were mapped by fluorescence in situ hybridization and Southern blot analysis and cloned using an IGHG (Cgamma) probe. The translocation linked the IGHG4 switch (Sgamma4) sequences of the productively rearranged allele to chromosome 1 sequences downstream of MUC1, leaving the MUC1 transcriptional unit intact. MUC1 was markedly overexpressed in the tumor at the mRNA and protein levels relative to lymphoma cell lines lacking a 1q21 rearrangement. Presumably, MUC1 transcription is aberrantly regulated by the IGHA (Calpha) 3' enhancer element retained on the same chromosome. Screening of a panel of B-cell lymphomas by Southern blot analysis identified a subset with a 3' MUC1 breakpoint and another with low-level amplification of MUC1. MUC-1 mucin has previously been shown to be frequently overexpressed in human epithelial cancers and to be associated with tumor progression and poor clinical outcome. Thus, MUC1 activation by chromosomal translocation, rearrangement, and amplification, identified here for the first time in NHL, is consistent with its suggested role in tumorigenesis. (Blood. 2000;95:2666-2671)
Gilles F, Goy A, Remache Y, et al. MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphoma. Blood. 2000; 95(9):2930-6 [PubMed] Related Publications
Cytogenetic abnormalities at chromosome 1q21 are among the most common lesions in diffuse large-cell lymphoma and have been associated with a poor prognosis. A novel cell line, SKI-DLCL-1, was established from ascitic fluid that carries a t(1;14)(q21;q32) chromosomal translocation. Using pulsed-field gel electrophoresis, the breakpoint on the IgH locus mapped to a gamma locus between Calpha(1) and Calpha(2). A cosmid library was prepared from SKI-DLCL-1, and Cgamma-positive clones spanning the breakpoint were identified by screening with fluorescence in situ hybridization. The breakpoint occurs 860 bp downstream of the 3' UTR of the MUC1 gene. The break appears to be a staggered double-strand break consistent with an error in immunoglobulin class switching. The MUC1 gene is highly transcribed and translated, and the protein is highly glycosylated. It is postulated that MUC1 expression is brought under the control of the 3'Ealpha enhancer. MUC1 lies in a region of chromosome 1 characterized by an unusually high density of genes, with 7 known genes in a region of approximately 85 kb. To determine whether there was a pleiotropic effect of the expression of genes in the region as a consequence of the translocation, the expression of 6 additional genes was assessed. None of the other genes in this region (CLK2, propin, COTE1, GBA, metaxin, and thrombospondin 3) are overexpressed in SKI-DLCL-1. Thus, the translocation t(1;14)(q21;q32) seen in both the primary tumor and the derived cell line results in the marked overexpression of MUC1 without affecting the expression of other genes in the region. (Blood. 2000;95:2930-2936)
Mucin 1 (MUC1) is a large complex glycoprotein that is highly expressed in breast cancer, and as such could be a target for immunotherapy. In mice, human MUC1 is highly immunogenic, particularly when conjugated to mannan, where a high frequency of CD8(+) MHC-restricted cytotoxic T lymphocytes is induced, accompanied by tumor protection. On this basis, a clinical trial was performed in which 25 patients with advanced metastatic carcinoma of breast, colon, stomach, or rectum received mannan-MUC1 in increasing doses. After 4 to 8 injections, large amounts of IgG1 anti-MUC1 antibodies were produced in 13 out of 25 patients (with antibody titers by ELISA of 1/320-1/20,480). Most of the antibodies reacted to the epitopes STAPPAHG and PAPGSTAP. In addition, T cell proliferation was found in 4 out of 15 patients, and CTL responses were seen in 2 out of 10 patients. Mannan-MUC1 can immunize patients, particularly for antibody formation, and to a lesser extent, cellular responses. It remains to be seen whether such responses have antitumor activity.
BACKGROUND: MUC1 and MUC3 are from a large family of glycoproteins with an aberrant expression profile in various malignancies. Much interest has been focused on the role of these proteins in the development and progression of colorectal cancer; however, no previous studies have included the highly confounding variable of vascular invasion in their survival analysis. Using high throughput tissue microarray technology we assessed the prognostic value of MUC1 and MUC3 expression in the largest cohort of colorectal cancer patients to date. We propose that tumours lacking expression of MUC1 and MUC3 will be more likely to metastasise, due to previously observed loss of cell-cell adhesion, and this will therefore lead to more aggressive cancers with poorer prognosis. METHODS: A tissue micro-array was prepared from tumour samples of 462 consecutive patients undergoing resection of a primary colorectal cancer. A comprehensive prospectively recorded data base with mean follow up of 75 months was collected and included common clinicopathological variables and disease specific survival. Immunohistochemical analysis of MUC1 and MUC3 expression was performed using antibodies NCL-MUC1 and 1143/B7 respectively, results were correlated with the variables within the database. RESULTS: Positive expression of MUC1 and MUC3 was seen in 32% and 74% of tumours respectively. On univariate analysis no correlation was seen with either MUC1 or MUC3 and any of the clinicopathological variables including tumour grade and stage, vascular invasion and tumour type. Kaplan-Meier analysis demonstrated a significant reduction in disease specific survival with MUC1 positive tumours (p = 0.038), this was not seen with MUC3 (p = 0.552). On multivariate analysis, using Cox proportional hazards model, MUC1 expression was shown to be an independent marker of prognosis (HR 1.339, 95%CI 1.002-1.790, p = 0.048). CONCLUSION: MUC1 expression in colorectal cancer is an independent marker of poor prognosis, even when vascular invasion is included in the analysis. These results support previous studies suggesting a role for MUC1 in colorectal cancer development possibly through its effects on cell adhesion.