Research IndicatorsGraph generated 31 August 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. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: VIM (cancer-related)
Kishore C, Sundaram S, Karunagaran DVitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells.
Chem Biol Interact. 2019; 309:108725 [PubMed
] Related Publications
Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells. Menadione showed cytotoxicity against human CRC cells (SW480 and SW620) and human primary colon cancer cells but was relatively ineffective against the cells from human normal colon (CRL-1790) and human primary colon epithelial cells. Menadione suppressed invasion, migration and epithelial-mesenchymal transition in human CRC cells by upregulating the expression of E-cadherin (CDH1), ZO-1 and downregulating that of N-cadherin (CDH2), Vimentin (VIM), ZEB1, MMP2 and MMP9. Menadione decreased TOPFlash/FOPFlash luciferase activity and expression of several downstream targets of Wnt signaling and coactivators such as β-catenin (CTNNB1), TCF7L2, Bcl9l, p300 (EP300) and cyclin D1 (CCND1) was suppressed. Menadione induced differentiation and increased apoptotic cell population in SubG0 phase of cell cycle in SW480 and SW620 cells. The ability of menadione to suppress EMT, migration, invasion, Wnt signaling, cell proliferation and induce Sub G0 arrest, highlights its potential to be considered for intensive preclinical and clinical investigation in CRC.
Sun LJ, Dong J, Gao F, et al.Intracranial solitary fibrous tumor: Report of two cases.
Medicine (Baltimore). 2019; 98(17):e15327 [PubMed
] Related Publications
RATIONALE: Intracranial solitary fibrous tumor (ISFT) is a rare spindle cell tumor derived from dendritic mesenchymal cells expressing CD34 antigens, which are widely distributed in human connective tissues.
PATIENT CONCERNS: In two case reports, we describe a 61-year-old woman and a 42-year-old man who present with intracranial malignant SFTs. Computed tomography or magnetic resonance imaging of head revealed that the largest size is about 3.3 × 3.0 cm in left occipital part and 4.0 × 3.0 cm in right skull base.
DIAGNOSIS: Postoperative pathological results demonstrated that all of two cases are SFT. Case one: Immunohistochemical examination demonstrated a strong immunoreaction for cluster of differentiation (CD)34, B-cell lymphoma 2 (Bcl-2) and Vimentin (Vim). Case two: The tumor was distinctively positive for Bcl-2, but not for CD34 and Vim.
INTERVENTIONS: One of the two patients recurred 6 years after the first tumor resection. After the recurrence, two gamma knife treatments were given, and another operation was performed about five years later. In one case, only tumor resection was performed.
OUTCOMES: Case one: The postoperative neurological status was substantially improved and regular follow-up examinations for 6 months postsurgery have shown that the patient is currently disease-free. Case two: The patient achieved a good outcome, with no epilepsy or other neurological symptoms experienced on a regular 6-month follow-up. The patient is currently disease free.
LESSONS: Imaging findings can be used to assist the diagnosis. The diagnostic method is pathology, and total surgical resection is the most effective treatment. The main treatment methods were total resection, supplemented by radiotherapy and chemotherapy if necessary.
Hu C, Li M, Guo T, et al.Anti-metastasis activity of curcumin against breast cancer via the inhibition of stem cell-like properties and EMT.
Phytomedicine. 2019; 58:152740 [PubMed
] Related Publications
BACKGROUND: Curcumin is a polyphenolic compound with potent chemopreventive and anti-cancer efficacy.
PURPOSE: To explore the potential anti-metastasis efficacy of curcumin in breast cancer stem-like cells (BCSCs), which are increasingly considered to be the origin of the recurrence and metastasis of breast cancer.
METHODS: A CCK8 assay was performed to evaluate cell viability, and a colony formation assay was conducted to determine cell proliferation in MCF-7 and MDA-MB-231 adherent cells. Transwell and wound healing assays were used to detect the effect of curcumin on cell migration and invasion in MDA-MB-231 cells. Mammospheres were cultured with serum free medium (SFM) for three generations and the BCSC surface marker CD44
RESULTS: Curcumin exhibited anti-proliferative and colony formation inhibiting activities in both the MCF-7 and MDA-MB-231 cell lines. It also suppressed the migration and invasion of MDA-MB-231 cells. The CD44
CONCLUSION: The results of the present study suggest that the inhibitor effects of curcumin on breast cancer cells may be related to resistance to cancer stem-like characters and the EMT process. These data indicate that curcumin could function as a type of anti-metastasis agent for breast cancer.
The incidence of recurrent t(6;9) translocation of the MYB proto‑oncogene to NFIB (the gene that encodes nuclear factor 1 B‑type) in adenoid cystic carcinoma (ACC) tumour tissues is high. However, MYB [the gene that encodes transcriptional activator Myb (MYB)] overexpression is more common, indicating that MYB serves a key role in ACC. The current study aimed to investigate the role of MYB in salivary (S)ACC growth and metastasis. A total of 50 fresh‑frozen SACC tissues and 41 fresh‑frozen normal submandibular gland (SMG) tissues were collected to measure MYB mRNA expression, and to analyse the associations between MYB and epithelial‑mesenchymal transition (EMT) markers. Compared with normal SMG tissue, SACC tissues demonstrated significantly increased MYB expression, with a high expression rate of 90%. Interestingly, MYB tended to be negatively correlated with CDH1 [the gene that encodes cadherin‑1 (E‑cadherin)] and positively correlated with VIM (the gene that encodes vimentin), suggesting that MYB is associated with SACC metastasis. To explore the role of MYB in SACC, the authors stably overexpressed and knocked down MYB in SACC cells. The authors of the current study demonstrated that MYB overexpression promoted SACC cell proliferation, migration and invasion, whereas its knockdown inhibited these activities. Additionally, when MYB was overexpressed, CDH1 expression was downregulated, and CDH2 (the gene that encodes cadherin‑2), VIM and ACTA2 (the gene that encodes actin, aortic smooth muscle) expression was upregulated. Then, the effect of MYB on lung tumour metastasis was investigated in vivo in non‑obese diabetic/severe combined immunodeficiency mice. MYB overexpressing and control cells were injected into the mice through the tail vein. The results revealed that MYB promoted SACC lung metastasis. Collectively, these results demonstrated that MYB is aberrantly overexpressed in SACC tissues, and promotes SACC cell proliferation and metastasis, indicating that MYB may be a novel therapeutic target for SACC.
Lu W, Luo JY, Wu MH, et al.Expression of vimentin in nasopharyngeal carcinoma and its possible molecular mechanism: A study based on immunohistochemistry and bioinformatics analysis.
Pathol Res Pract. 2019; 215(5):1020-1032 [PubMed
] Related Publications
BACKGROUND: Although previous researchers have analyzed the expression level of vimentin in nasopharyngeal carcinoma (NPC), the sample size of each study was too small, and there was no further in-depth study utilizing microarray and RNA-sequencing data. More importantly, the role and molecular mechanism of vimentin in NPC have not yet been addressed comprehensively. Accordingly, the aim of the present research was to conduct a full exploration of the clinical significance of vimentin in NPC in a large sample size.
MATERIALS AND METHODS: Immunohistochemistry was used to test the expression of vimentin in clinical samples. Data from relevant microarray and RNA-sequencing datasets were screened and extracted to explore the clinical role of vimentin in NPC. Subsequently, vimentin-related signaling pathways were investigated via in-silico approaches.
RESULTS: The clinical immunohistochemistry detection showed the positive expression ratio of vimentin was 24.6% (14/57) of the NPC specimens, whereas vimentin expression was negative in nasopharyngitis (NPG) tissues (0/20, P = 0.016). The mRNA and protein levels of vimentin were both remarkably up-regulated in NPC based on 196 and 1566 cases, respectively. The protein level of vimentin was also a risky factor for the prognosis prediction of NPC with the hazard ratios (HR) being 3.831. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses, the localization of vimentin was in both the cytoplasm and the cytoskeleton, and vimentin was involved in the regulation of molecular function, the execution phase of apoptosis, and the regulation of cellular component organization.
CONCLUSION: The high expression of vimentin plays a pivotal role in the development and poor progression of NPC, which indicates that vimentin may be an effective predictive indicator for NPC.
Shirkavand A, Boroujeni ZN, Aleyasin SAExamination of methylation changes of
Indian J Cancer. 2018 Oct-Dec; 55(4):366-371 [PubMed
] Related Publications
BACKGROUND: Studying whole blood DNA methylation as a risk marker has valuable applications in either diagnosis or staging of breast cancer. We investigated whole blood DNA methylation status of VIM, CXCR4, DOK7, and SPDEF genes in breast cancer patients in comparison to healthy control subjects.
MATERIALS AND METHODS: 60 patients with breast cancer and 40 healthy controls were examined. Genomic DNA isolated from peripheral blood and restriction enzyme polymerase chain reaction (REP) method was applied for analysis. Real-time PCR was used to confirm methylation status of the aforementioned genes and therefore to find out the methylation differences between normal and breast cancer subjects.
RESULTS: Level of DOK7 promoter hypomethylation in normal and breast cancer samples was significant (P-value = 0.001). The study, also, showed that hypomethylation of VIM and CXCR4 genes are significant in patients compared with normal cases (P-value < 0.05). Furthermore, SPDEF promoter hypomethylation was not significantly differed between normal and breast cancer samples (P-value = 0.2).
CONCLUSIONS: Hypermethylation of DOK7 gene in DNA from patients affected with breast cancer offers a biomarker for diagnosis of the breast cancer. This study indicates that methylation status of VIM and CXCR4 genes changes in breast cancer; so, they can be used as molecular biomarkers in breast cancer prognosis.
Wachsmannova L, Stevurkova V, Ciernikova SChanges in SNAI1 and VIM gene expression in Caco2 cells after cocultivation with bacteria from colorectal cancer biopsies.
Neoplasma. 2019; 66(2):271-275 [PubMed
] Related Publications
The development of distant metastases is the final stage in the progression of solid cancer and is responsible for the majority of cancer-related deaths. Epithelial-mesenchymal transition (EMT) is involved in cancer progression and metastasis. In the present study we used different types of intracellular bacteria isolated from colorectal cancer biopsies to examine their effect on the expression of SNAI1 and VIM genes in Caco2 cell line. SNAI1 gene expression was significantly decreased after cocultivation of Caco2 cells with Pseudomonas aeruginosa, Proteus vulgaris, Proteus mirabilis, Enterococcus faecalis, Klebsiella pneumoniae and Bacillus cereus, respectively (P<0.05). We observed more than 2-fold increase in VIM gene expression within Caco2 cells after cocultivation with Proteus vulgaris. On the other hand, VIM gene expression decreased by half after cocultivation with Pseudomonas aeruginosa and Proteus mirabilis (P<0.05). Our data suggest bacteria presented in colorectal carcinoma tissues may cause changes in gene expression of EMT-associated genes. Further research is needed to find out whether bacteria are capable to support EMT and cancer progression.
Qin Y, Yu J, Zhang M, et al.ZEB1 promotes tumorigenesis and metastasis in hepatocellular carcinoma by regulating the expression of vimentin.
Mol Med Rep. 2019; 19(3):2297-2306 [PubMed
] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and its prognosis remains poor. Epithelial‑to‑mesenchymal transition (EMT)‑induced markers have emerged as key regulators of tumor development and progression in HCC. The aim of the present study was to investigate the role of zinc finger E‑box‑binding homeobox 1 (ZEB1) in the tumorigenesis of HCC and to elucidate the mechanism underlying the correlation between ZEB1 and vimentin (VIM). The expression levels of ZEB1 and VIM were assessed by immunohistochemistry, western blotting and reverse transcription‑quantitative polymerase chain reaction analysis in HCC tissues and cell lines. The biological significance of ZEB1 was examined by downregulating the expression of ZEB1 in Huh‑7 cells. A luciferase reporter assay was used to investigate the association between ZEB1 and VIM. The expression levels of ZEB1 and VIM were higher in tumor tissues compared with those in adjacent normal tissues, and they were significantly associated with a poor prognosis in patients with HCC, whereas ZEB1 silencing led to the attenuation of HCC cell proliferation, invasion and migration. Furthermore, it was observed that ZEB1 was able to bind to a certain site in the VIM promoter and regulate the transcriptional activity of VIM. Therefore, the present study demonstrated that ZEB1 is a potential biomarker of the tumorigenesis and progression of HCC, and it may regulate transcription of the VIM gene.
PPP3CB belongs to the phosphoprotein phosphatases (PPPs) group. Although the majority of the PPP family play important roles in the epithelial-to-mesenchymal transition (EMT) of tumor cells, little is known about the function of PPP3CB in the EMT process. Here, we found PPP3CB had high expression in kidney mesenchymal-like cells compared with kidney epithelial-like cells. Knock-down of PPP3CB downregulated epithelial marker E-cadherin and upregulated mesenchymal marker Vimentin, promoting the transition of cell states from epithelial to mesenchymal and reorganizing the actin cytoskeleton which contributed to cell migration. Conversely, overexpression of PPP3CB reversed EMT and inhibited migration of tumor cells. Besides, in vitro and in vivo experiments indicated that the loss of PPP3CB suppressed the tumor growth. However, the deletion of the phosphatase domain of PPP3CB showed no effect on the expression of E-cadherin, migration, and G401 cell proliferation. Together, we demonstrate that PPP3CB inhibits G401 cell migration through regulating EMT and promotes cell proliferation, which are both associated with the phosphatase activity of PPP3CB.
Savci-Heijink CD, Halfwerk H, Hooijer GKJ, et al.Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior.
Breast Cancer Res Treat. 2019; 174(3):649-659 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) has been implicated as an important step in the development of distant metastases. We therefore wished to study EMT status of primary breast carcinomas from patients who during follow-up developed distant metastases.
METHODS: mRNA expression profiles of primary breast carcinoma samples (n = 151) from patients who developed metastatic disease were analyzed and EMT status was designated using a previously described EMT-core signature. EMT status of the primary tumor was correlated to clinicopathological characteristics, molecular subtypes, metastasis pattern, chemotherapy response and survival outcomes. In addition, using immunohistochemistry, the expression levels of several proteins implicated in EMT were studied (CDH1, CDH2, NAT1, SNAI2, TWIST1, VIM, and ZEB1) compared with the designated EMT status and survival.
RESULTS: Utilizing the 130-gene-EMT-core signature, 66.2% of the primary tumors in the current study was assessed as EMT-activated. In contrast to our expectations, analyses revealed that 84.6% of Luminal A tumors, 65.1% of Luminal B tumors, and 55.6% of HER2-like had an activated EMT status, compared to only 25% of the basal-type tumors (p < 0.001). EMT status was not correlated to the pattern of metastatic disease, metastasis-specific survival, and overall survival. Similarly, there was not a significant association between EMT status of the primary tumor and chemotherapy response in the metastatic setting. Immunostaining for NAT1 and TWIST1 correlated with the EMT status (p 0.003 and p 0.047, respectively). Multivariate analyses showed that NAT1 and TWIST1 staining was significantly associated with EMT status regardless of the estrogen receptor status of the tumors (p values: 0.020 and 0.027, respectively).
CONCLUSIONS: The EMT status of breast cancers, as defined by the presence of a core EMT gene expression signature is associated with non-basal-type tumors, but not with the pattern of distant metastasis. Of several potential immunohistochemical EMT markers, only NAT1 and TWIST1 expression levels were associated with the gene expression-based EMT status.
MicroRNA‑21 (miR‑21) has been revealed to play a crucial role in regulating the biological behavior, including proliferation, migration, invasion and metastasis in certain cancers. However, its role in esophageal squamous cell carcinoma (ESCC) has yet to be elucidated. Based on the data of GSE13937 downloaded from Gene Expression Omnibus (GEO) database, miR‑21 was revealed to be one of the top 20 differentially expressed (DE) miRNAs screened using the Morpheus online tool. RAS p21 protein activator 1 (RASA1) was predicted as the target gene of miR‑21 using the predicting software and was combined with miR‑21 using the luciferase reporter assay. Its relative expression was significantly decreased, however, miR‑21 was increased in the tumor tissues compared to the normal adjacent tissues in patients with ESCC as determined by quantitative polymerase chain reaction (q‑PCR). Furthermore, overexpression of miR‑21 (mimic) could significantly decrease the gene level of RASA1. Conversely, downregulation of miR‑21 (inhibitor) significantly increased the gene level of RASA1, while downregulation of RASA1 (siRASA1) markedly increased the gene expression of miR‑21. Notably, the expression of Snail and vimentin were significantly increased by upregulation of miR‑21 and downregulation of RASA1. Transwell results revealed that miR‑21 and RASA1 regulated proliferation, migration and invasion in ESCC cells. In an in vivo model, miR‑21 inhibitor (antagomir) could inhibit tumor growth. In conclusion, miR‑21 regulated cell proliferation, migration, invasion and tumor growth of ESCC by directly targeting RASA1, which may have been achieved via regulation of Snail and vimentin. Anti‑miR‑21 revealed an antitumor effect. Thus, it may be considered as a possible target for ESCC therapy.
Lactate dehydrogenase A (LDH-A) is a key enzyme during glycolysis, which increases the synthesis of related proteins and has elevated activity in cancer cells. The role of LDH-A in lung adenocarcinoma (LUAD) progression was investigated in the present study. Expression levels of LDH-A were assessed in LUAD samples, and the relationship between LDH-A expression status and the prognosis of LUAD patients was confirmed. The effect of LDH-A on proliferation, invasion, migration, and colony formation of cancer cells was assessed. We further determined the role of LDH-A in tumor growth
A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive ([Formula: see text]) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative ([Formula: see text]) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.
Kakurina GV, Kondakova IV, Spirina LV, et al.Expression of Genes Encoding Cell Motility Proteins during Progression of Head and Neck Squamous Cell Carcinoma.
Bull Exp Biol Med. 2018; 166(2):250-252 [PubMed
] Related Publications
The model of head and neck squamous cell carcinoma (HNSCC) was used to study the expression of genes encoding actin-binding proteins depending on the type of cell motility. The expression of SNAIL1 and CAPN2 mRNA in HNSCC tissue was higher than in specimens of dysplastic epithelium of the larynx and hypopharynx, which can be explained by activation of mesenchymal and amoeboid types of cell motility. In biopsy material of HNSCC patients with T1-2N0M0, expression of genes responsible for actin-binding proteins differed from that of patients with pretumor pathology of the larynx and hypopharynx: expression of FSCN was lower, while expressions of EZR and CAP1 were higher. The data attest that progression of HNSCC is associated with activation of both types of cell motility and with the changes in the expression of mRNA encoding cell motility proteins.
Horibe T, Torisawa A, Masuda Y, Kawakami KFunctional analysis of protein disulfide isomerase P5 in glioblastoma cells as a novel anticancer target.
Oncol Rep. 2019; 41(2):961-972 [PubMed
] Related Publications
P5, which is a member of the protein disulfide isomerase family, possesses isomerase and chaperone activity in vitro; however, the physiological functions of this enzyme in cells remain unclear. To understand the important roles of P5 in cancer cells, the present study examined its expression on the surface of normal and cancer cell lines by flow cytometry using an affinity‑purified anti‑P5 antibody labeled with 6‑(fluorescein‑5‑carboxamido) hexanoic acid succinimidyl ester. P5 expression was increased on the surface of various cancer cell lines, including leukemia cells, and glioblastoma, breast, colon, ovarian and uterine cervical cancer cells, compared with normal cells. However, P5 was constantly expressed within both normal and cancer cell lysates, and its total expression levels were not significantly different between the cells. P5 knockdown in glioblastoma cells by small interfering RNA affected Bip promoter activation during cancer cell growth, and significantly inhibited cancer cell growth and migration. Immunoprecipitation using an anti‑P5 antibody in cancer and normal cells demonstrated that vimentin was bound to P5, predominantly in U251 glioblastoma cells. P5 knockdown in glioblastoma cells did not affect the protein expression levels of vimentin; however, it did affect the expression of numerous epithelial‑mesenchymal transition markers, including Snail and Slug. These results suggested that P5 may serve an important role in cancer cell growth, and may be considered an attractive and potent target for the treatment of glioblastoma.
Zhou W, Gong L, Wu Q, et al.PHF8 upregulation contributes to autophagic degradation of E-cadherin, epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma.
J Exp Clin Cancer Res. 2018; 37(1):215 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Plant homeodomain finger protein 8 (PHF8) serves an activator of epithelial-mesenchymal transition (EMT) and is implicated in various tumors. However, little is known about PHF8 roles in hepatocellular carcinoma (HCC) and regulating E-cadherin expression.
METHODS: PHF8 expression pattern was investigated by informatic analysis and verified by RT-qPCR and immunochemistry in HCC tissues and cell lines. CCK8, xenograft tumor model, transwell assay, and tandem mCherry-GFP-LC3 fusion protein assay were utilized to assess the effects of PHF8 on proliferation, metastasis and autophagy of HCC cells in vitro and in vivo. ChIP, immunoblot analysis, rescue experiments and inhibitor treatment were used to clarify the mechanism by which PHF8 facilitated EMT, metastasis and autophagy.
RESULTS: PHF8 upregulation was quite prevalent in HCC tissues and closely correlated with worse overall survival and disease-relapse free survival. Furthermore, PHF8-knockdown dramatically suppressed cell growth, migration, invasion and autophagy, and the expression of SNAI1, VIM, N-cadherin and FIP200, and increased E-cadherin level, while PHF8-overexpression led to the opposite results. Additionally, FIP200 augmentation reversed the inhibited effects of PHF8-siliencing on tumor migration, invasion and autophagy. Mechanistically, PHF8 was involved in transcriptionally regulating the expression of SNAI1, VIM and FIP200, rather than N-cadherin and E-cadherin. Noticeably, E-cadherin degradation could be accelerated by PHF8-mediated FIP200-dependent autophagy, a crucial pathway complementary to transcriptional repression of E-cadherin by SNAI1 activation.
CONCLUSION: These findings suggested that PHF8 played an oncogenic role in facilitating FIP200-dependent autophagic degradation of E-cadherin, EMT and metastasis in HCC. PHF8 might be a promising target for prevention, treatment and prognostic prediction of HCC.
Le AV, Szaumkessel M, Tan TZ, et al.DNA Methylation Profiling of Breast Cancer Cell Lines along the Epithelial Mesenchymal Spectrum-Implications for the Choice of Circulating Tumour DNA Methylation Markers.
Int J Mol Sci. 2018; 19(9) [PubMed
] Free Access to Full Article Related Publications
(1) Background: Epithelial⁻mesenchymal plasticity (EMP) is a dynamic process whereby epithelial carcinoma cells reversibly acquire morphological and invasive characteristics typical of mesenchymal cells. Identifying the methylation differences between epithelial and mesenchymal states may assist in the identification of optimal DNA methylation biomarkers for the blood-based monitoring of cancer. (2) Methods: Methylation-sensitive high-resolution melting (MS-HRM) was used to examine the promoter methylation status of a panel of established and novel markers in a range of breast cancer cell lines spanning the epithelial⁻mesenchymal spectrum. Pyrosequencing was used to validate the MS-HRM results. (3) Results:
Natarajan S, Sumantran VN, Ranganathan M, Madheswaran SMicroarray and pattern miner analysis of AXL and VIM gene networks in MDA‑MB‑231 cells.
Mol Med Rep. 2018; 18(4):4147-4155 [PubMed
] Related Publications
MDA‑MB‑231 cells represent malignant triple‑negative breast cancer, which overexpress epidermal growth factor receptor (EGFR) and two genes (AXL and VIM) associated with poor prognosis. The present study aimed to identify novel therapeutic targets and elucidate the functional networks for the AXL and VIM genes in MDA‑MB‑231 cells. We identified 71 genes upregulated in MDA‑MB‑231 vs. MCF7 cells using BRB‑Array tool to re‑analyse microarray data from six GEO datasets. Gene ontology and STRING analysis showed that 43/71 genes upregulated in MDA‑MB‑231 compared with MCF7 cells, regulate cell survival and migration. Another 19 novel genes regulate migration, metastases, senescence, autophagy and chemoresistance. The Pattern Miner systems biology tool uses specific genes as inputs or 'baits' to identify outputs from the NCI‑60 database. Using five genes regulating cancer cell migration (AXL, VIM, EGFR, CAPN2, and COL4A1) as input 'baits', we used pattern miner to identify statistically significant, co‑expressed genes from the list of 71 genes upregulated in MDA‑MB‑231 compared with MCF7 cells. Outputs were subsets of the 71 genes, which showed significant co‑expression with one or more of the five input genes. These outputs were used to develop functional networks for AXL and VIM. Analysis of these networks verified known properties of AXL and VIM, and suggested novel functions for these two genes. Thus, genes in the AXL network promote migration, metastasis and chemoresistance, whereas the VIM gene network regulates novel tumorigenic processes, such as lipogenesis, senescence and autophagy. Notably, these two networks contain 12 genes not reported for TNBC.
Weng CH, Chen LY, Lin YC, et al.Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI.
Oncogene. 2019; 38(4):455-468 [PubMed
] Related Publications
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is a major advance in treating NSCLC with EGFR-activating mutations. However, acquired resistance, due partially to secondary mutations limits their use. Here we report that NSCLC cells with acquired resistance to gefitinib or osimertinib (AZD9291) exhibit EMT features, with a decrease in E-cadherin, and increases in vimentin and stemness, without possessing any EGFR secondary mutations. Knockdown of E-cadherin in parental cells increased gefitinib resistance and stemness, while knockdown of vimentin in resistant cells resulted in opposite effects. Src activation and Hakai upregulation were found in gefitinib-resistant cells. Knockdown of Hakai elevated E-cadherin expression, attenuated stemness, and resensitized the cells to gefitinib. Clinical cancer specimens with acquired gefitinib resistance also showed a decrease in E-cadherin and an increase in Hakai expression. The dual HDAC and HMGR inhibitor JMF3086 inhibited the Src/Hakai and Hakai/E-cadherin interaction to reverse E-cadherin expression, and attenuated vimentin and stemness to restore gefitinib sensitivity. The EMT features of AZD9291-resistant H1975 cells were related to the upregulation of Zeb1. Both gefitinib and AZD9291 sensitivity was restored by JMF3086 through reversing EMT. Our study not only revealed a common mechanism of EMT in both gefitinib and AZD9291 resistance beyond EGFR mutations per se, but also provides a new strategy to overcome it.
A large number of tumor-related methylated genes have been suggested to be of diagnostic and prognostic values for CRC when analyzed in patients' stool samples; however, reported sensitivities and specificities have been inconsistent and widely varied. This meta-analysis was conducted to assess the detection accuracy of stool DNA methylation assay in CRC, early stages of CRC (advanced adenoma, non-advanced adenomas) and hyperplastic polyps, separately. We searched MEDLINE, Web of Science, Scopus and Google Scholar databases until May 1, 2016. From 469 publications obtained in the initial literature search, 38 studies were included in the final analysis involving 4867 individuals. The true positive, false positive, true negative and false negative of a stool-based DNA methylation biomarker using all single-gene tests considering a certain gene; regardless of a specific gene were pooled and studied in different categories. The sensitivity of different genes in detecting different stages of CRC ranged from 0% to 100% and the specificities ranged from 73% to 100%. Our results elucidated that SFRP1 and SFRP2 methylation possessed promising accuracy for detection of not only CRC (DOR: 31.67; 95%CI, 12.31-81.49 and DOR: 35.36; 95%CI, 18.71-66.84, respectively) but also the early stages of cancer, adenoma (DOR: 19.72; 95%CI, 6.68-58.25 and DOR: 13.20; 95%CI, 6.01-28.00, respectively). Besides, NDRG4 could be also considered as a significant diagnostic marker gene in CRC (DOR: 24.37; 95%CI, 10.11-58.73) and VIM in adenoma (DOR: 15.21; 95%CI, 2.72-85.10). In conclusion, stool DNA hypermethylation assay based on the candidate genes SFRP1, SFRP2, NDRG4 and VIM could offer potential diagnostic value for CRC based on the findings of this meta-analysis.
Wang Y, Ding X, Hu H, et al.Long non-coding RNA lnc-PCTST predicts prognosis through inhibiting progression of pancreatic cancer by downregulation of TACC-3.
Int J Cancer. 2018; 143(12):3143-3154 [PubMed
] Related Publications
Pancreatic cancer (PC), which is one of the most lethal of malignancies and a major health burden, is associated with a dismal prognosis despite current therapeutic advances. Numerous long noncoding RNAs (lncRNA) have shown to be essential for PC tumorigenesis and progression. Nevertheless, the exact expression pattern of lnc-PCTST and its clinical significance still remain unclear. This study investigates the expression pattern of lnc-PCTST and its associated mRNA in three paired PC tissues and adjacent non-tumor tissues by Microarray-coarray approach. Briefly, our data demonstrated that lnc-PCTST expression is down-regulated in PC tissues. Also, lnc-PCTST has shown to be negatively correlated with transforming acidic coiled-coil 3 (TACC-3) expression. This expression pattern was further confirmed following qRT-PCR validation of 34 out of 48 paired cancer tissues. Furthermore, lnc-PCTST overexpression in PC cell lines inhibited cell proliferation and invasion in vitro, and tumorigenesis in vivo (using nude mice as animal model), but did not altered cell migration. Moreover, lnc-PCTST overexpression increased E-cadherin and repressed vimentin expression in vitro. Additionally, TACC-3 knockdown simulated the inhibiting effect of lnc-PCTST overexpression on PC cell lines, and the impaired proliferation, invasion effect and E-cadherin, vimentin expression on lnc-PCTST over-expressed cell lines can be rescued by overexpressed TACC-3. Significantly, the expression of lnc-PCTST was closely associated with its genomic neighboring gene TACC-3 and inhibited its promoter activity. In conclusion, lnc-PCTST is a potential tumor suppressor in PC, which inhibits cell proliferation, invasion, tumorigenesis and EMT by modulating TACC-3.
BACKGROUND: Peritoneal dissemination (PD) is one of the most common causes of cancer-related mortality in gastric cancer (GC). We aimed to identify PD-associated genes and investigate their role in GC.
MATERIALS AND METHODS: We identified FGFR1 as a putative PD-associated gene using a bioinformatics approach. The biological significance of FGFR1 in epithelial-to-mesenchymal transition (EMT) was evaluated according to the correlation with genes that participated in EMT and FGFR1 knockdown experiments. The associations between FGFR1 expression and the clinicopathological features were examined.
RESULTS: FGFR1 expression positively correlated with SNAI1, VIM and ZEB1 expression, and negatively correlated with CDH1 expression. Knockdown of FGFR1 suppressed the malignant phenotype of GC cells. High FGFR1 expression significantly correlated with the peritoneal lavage cytology and synchronous PD positivity as well as poor prognosis.
CONCLUSION: High FGFR1 expression was associated with PD via promotion of EMT and led to a poor prognosis of GC patients.
Bai J, Yeh S, Qiu X, et al.TR4 nuclear receptor promotes clear cell renal cell carcinoma (ccRCC) vasculogenic mimicry (VM) formation and metastasis via altering the miR490-3p/vimentin signals.
Oncogene. 2018; 37(44):5901-5912 [PubMed
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While TR4 nuclear receptor plays key roles to promote prostate cancer progression, its roles to alter the progression of clear cell renal cell carcinoma (ccRCC), remains unclear. Here, we demonstrate that TR4 can promote the ccRCC cell vasculogenic mimicry (VM) formation and its associated metastasis via modulating the miR490-3p/vimentin (VIM) signals. Mechanism dissection revealed that TR4 might increase the oncogene VIM expression via decreasing the miR-490-3p expression through direct binding to the TR4-response-elements (TR4REs) on the promoter region of miR-490-3p, which might then directly target the 3' UTR of VIM-mRNA to increase its protein expression. Preclinical studies using the in vivo mouse model with xenografted RCC Caki-1 cells into the sub-renal capsule of nude mice also found that TR4 could promote the ccRCC VM and its associated metastasis via modulating the miR490-3p/VIM signals. Together, results from preclinical studies using multiple RCC cell lines and the in vivo mouse model all conclude that TR4 may play a key role to promote ccRCC VM formation and metastasis and targeting the newly identified TR4/miR-490-3p/VIM signals with small molecules may help us to develop a new therapeutic approach to better suppress the ccRCC metastasis.
Arzi L, Riazi G, Sadeghizadeh M, et al.A Comparative Study on Anti-Invasion, Antimigration, and Antiadhesion Effects of the Bioactive Carotenoids of Saffron on 4T1 Breast Cancer Cells Through Their Effects on Wnt/β-Catenin Pathway Genes.
DNA Cell Biol. 2018; 37(8):697-707 [PubMed
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Crocus sativus L. (saffron) has been used as a spice and as a medicine for the past four thousand years. Recently, saffron has been well documented to possess anticancer effects on primary tumors. However studies of its antimetastatic potential are lacking. The present study is a comparative investigation of the antimetastatic effects of saffron carotenoids, crocin and crocetin, on triple negative metastatic breast cancer cells (4T1) and their effects on the Wnt/β-catenin pathway. It was found that treatment of 4T1 cells with crocin and crocetin resulted in the inhibition of viability in a dose-dependent manner. Scratch and Transwell chamber assays showed that the nontoxic doses of crocin and crocetin significantly inhibited migration, cell mobility, and invasion, also attenuating adhesion to extracellular matrix. Crocin downregulated mRNA expression of FZD7, NEDD9, VIM, and VEGF-α genes and upregulated E-CAD. Crocin and crocetin exhibited comparable anti-invasion properties on 4T1 cells. However, crocin and crocetin exerted more pronounced antimigration and antiadhesion potency, respectively. Furthermore, we showed that the antimetastatic effects of crocin can occur through interfering with the Wnt/β-catenin pathway.
BACKGROUND: Vimentin (VIM) is a type III intermediate filament that maintains cell integrity, and is involved in cell migration, motility and adhesion. When overexpressed in solid cancers, vimentin drives epithelial to mesenchymal transition (EMT) and ultimately, metastasis. The effects of its overexpression in AML are unclear.
METHODS: In this study, we analyzed the TCGA data of 173 AML patients for which complete clinical and expression data were available. In this analysis, we assessed the association between VIM mRNA expression and patient's clinical and molecular characteristics including clinical outcome.
RESULTS: VIM overexpression was associated with higher white blood count (< p = 0.0001). Patients with high VIM expression have worse overall survival (OS) and disease-free survival (DFS) compared with patients with low VIM expression (median OS; 7.95 months vs 19.2 months; p = 0.029). After age-stratification, high VIM expression was significantly associated with worse overall survival in older patients (age ≥ 60; median OS: 5.4 vs 9.9 months: p = 0.0257) but not in younger patients (age < 60). In stratification analysis according to cytogenetic status, high VIM expression was significantly associated with shorter OS (7.95 vs 24.6 months: p = 0.0102) in cytogenetically normal, but not in cytogenetic abnormal AML.
CONCLUSIONS: Collectively, the data indicate that overexpression of the EMT marker vimentin is associated with poor clinical outcome in older patients with cytogenetically normal AML; and therefore may play a role in this disease.
Chen M, Xia Z, Chen C, et al.LncRNA MALAT1 promotes epithelial-to-mesenchymal transition of esophageal cancer through Ezh2-Notch1 signaling pathway.
Anticancer Drugs. 2018; 29(8):767-773 [PubMed
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To investigate effect of long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on epithelial-to-mesenchymal transition (EMT) of esophageal cancer (EC) and role of enhancer of zeste homolog 2 (Ezh2)-Notch1 signaling pathway in the process. The expression of MALAT1 was determined in four EC cell lines by real-time PCR. TE-1 and EC109 cells were transfected with sh-MALAT1 to inhibit expression of MALAT1 or transfected with pcDNA3.1-Ezh2 to overexpress Ezh2. Invasion and migration assays were conducted to analyze cell metastasis, and expressions of Ezh2-Notch1 signaling-related proteins as well as EMT related proteins were determined using both real-time PCR and western blot. MALAT1 was significantly up-regulated in all EC cell lines compared with the normal cells. Silencing MALAT1 using shRNA could significantly inhibit cell viability (reduced almost 30% of cell viability compared with the control), invasion (reduced almost 30% of cell migration compared with the control), and migration (reduced almost 50% of cell migration compared with the control) of both TE-1 and EC109 cells (P<0.05). Meanwhile, expression of Ezh2, Notch1, Hes1, MMP-9, and Vimentin was significantly decreased and expression of E-cadherin was significantly increased when cells were transfected with sh-MALAT1 compared with the nontransfected cells (P<0.05). However, when cells were cotransfected with both sh-MALAT1 and pcDNA3.1-Ezh2, the protein expression changes induced by sh-MALAT1 were recovered. MALAT1 could affect EMT and metastasis of EC cells through Ezh2-Notch1 signaling pathway. This study can give deeper understandings of the role of MALAT1 in EC and may provide some new directions for treatment of patients with EC.
Raschioni C, Bottai G, Sagona A, et al.CXCR4/CXCL12 Signaling and Protumor Macrophages in Primary Tumors and Sentinel Lymph Nodes Are Involved in Luminal B Breast Cancer Progression.
Dis Markers. 2018; 2018:5018671 [PubMed
] Free Access to Full Article Related Publications
Luminal B breast cancers (BC) have a more aggressive behavior associated with a higher rate of tumor relapse and worse prognosis compared to luminal A tumors. In this study, we evaluated the involvement of specific epithelial-to-mesenchymal transition- (EMT-) and immune-related pathways in the dissemination of luminal B BC cells. The expression of 42 EMT- and immune-related genes was evaluated in matched sentinel lymph nodes (SLNs) analyzed by the one-step nucleic acid amplification assay (OSNA) and primary tumors of 40 luminal B BC patients by gene array and immunohistochemistry. The results were validated in an independent group of 150 luminal B tumors by immunohistochemistry and immunofluorescence and using gene expression data from 315 luminal B BC patients included in the Metabric dataset. We found that the expression of
Deng Q, Jiang G, Wu Y, et al.GPER/Hippo-YAP signal is involved in Bisphenol S induced migration of triple negative breast cancer (TNBC) cells.
J Hazard Mater. 2018; 355:1-9 [PubMed
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Nowadays, risk factors of triple-negative breast cancer (TNBC) metastasis are not well identified. Our present study reveals that an industrial chemical, bisphenol S (BPS), can promote the migration, but not the proliferation, of TNBC cells in vitro. BPS activates YAP, a key effector of Hippo pathway, by inhibiting its phosphorylation, which promotes YAP nuclear accumulation and up-regulates its downstream genes such as CTGF and ANKRD1. Inhibition of YAP blocks the BPS-triggered cell migration and up-regulation of fibronectin (FN) and vimentin (Vim). BPS rapidly decreases the phosphorylation levels of LATS1 (Ser909) in TNBC cells, which regulates the activation and functions of YAP. Silencing LATS1/2 by siRNA increases BPS-induced dephosphorylation of YAP and extended the half-life of YAP protein. Inhibition of G protein-coupled estrogen receptor 1 (GPER) and its downstream PLCβ/PKC signals attenuate the effects of BPS-induced YAP dephosphorylation and CTGF up-regulation. Targeted inhibition of GPER/YAP inhibits BPS-induced migration of TNBC cells. Collectively, we reveal that GPER/Hippo-YAP signal is involved in BPS-induced migration of TNBC cells.
BACKGROUND: Nucleoporin Nup88, a component of nuclear pore complexes, is known to be overexpressed in several types of tumor tissue. The overexpression of Nup88 has been reported to promote the early step of tumorigenesis by inducing multinuclei in both HeLa cells and a mouse model. However, the molecular basis of how Nup88 leads to a multinucleated phenotype remains unclear because of a lack of information concerning its binding partners. In this study, we characterize a novel interaction between Nup88 and vimentin. We also examine the involvement of vimentin in the Nup88-dependent multinucleated phenotype.
METHODS: Cells overexpressing tagged versions of Nup88, vimentin and their truncations were used in this study. Coprecipitation and GST-pulldown assays were carried out to analyze protein-protein interactions. Vimentin knockdown by siRNA was performed to examine the functional role of the Nup88-vimentin interaction in cells. The phosphorylation status of vimentin was analyzed by immunoblotting using an antibody specific for its phosphorylation site.
RESULTS: Vimentin was identified as a Nup88 interacting partner, although it did not bind to other nucleoporins, such as Nup50, Nup214, and Nup358, in HeLa cell lysates. The N-terminal 541 amino acid residues of Nup88 was found to be responsible for its interaction with vimentin. Recombinant GST-tagged Nup88 bound to recombinant vimentin in a GST-pulldown assay. Although overexpression of Nup88 in HeLa cells was observed mainly at the nuclear rim and in the cytoplasm, colocalization with vimentin was only partially detected at or around the nuclear rim. Disruption of the Nup88-vimentin interaction by vimentin specific siRNA transfection suppressed the Nup88-dependent multinucleated phenotype. An excess amount of Nup88 in cell lysates inhibited the dephosphorylation of a serine residue (Ser83) within the vimentin N-terminal region even in the absence and presence of an exogenous phosphatase. The N-terminal 96 amino acid residues of vimentin interacted with both full-length and the N-terminal 541 residues of Nup88.
CONCLUSIONS: Nup88 can affect the phosphorylation status of vimentin, which may contribute to the Nup88-dependent multinucleated phenotype through changing the organization of vimentin.