Gene Summary

Gene:GMNN; geminin DNA replication inhibitor
Aliases: Gem, MGORS6
Summary:This gene encodes a protein that plays a critical role in cell cycle regulation. The encoded protein inhibits DNA replication by binding to DNA replication factor Cdt1, preventing the incorporation of minichromosome maintenance proteins into the pre-replication complex. The encoded protein is expressed during the S and G2 phases of the cell cycle and is degraded by the anaphase-promoting complex during the metaphase-anaphase transition. Increased expression of this gene may play a role in several malignancies including colon, rectal and breast cancer. Alternatively spliced transcript variants have been observed for this gene, and two pseudogenes of this gene are located on the short arm of chromosome 16. [provided by RefSeq, Oct 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Up-Regulation
  • Mitosis
  • Cell Cycle
  • Cohort Studies
  • Protein-Serine-Threonine Kinases
  • Down-Regulation
  • Cancer Gene Expression Regulation
  • Ubiquitin-Protein Ligases
  • Young Adult
  • Immunohistochemistry
  • Mutation
  • Restriction Fragment Length Polymorphism
  • Cell Cycle Proteins
  • Base Sequence
  • Chromosome 6
  • Ovarian Cancer
  • MKI67
  • Aneuploidy
  • Gene Expression Profiling
  • DNA-Binding Proteins
  • Nuclear Proteins
  • alpha Karyopherins
  • Substrate Specificity
  • Signal Transduction
  • Histones
  • Biomarkers, Tumor
  • Neoplastic Cell Transformation
  • DNA Replication
  • Cultured Cells
  • Genomic Instability
  • Geminin
  • Messenger RNA
  • Protein Conformation
  • Cell Proliferation
  • Minichromosome Maintenance Complex Component 2
  • Adolescents
  • Liver Cancer
  • DNA Damage
  • MicroRNAs
  • Breast Cancer
  • Oligonucleotide Array Sequence Analysis
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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).

Latest Publications: GMNN (cancer-related)

Imafuji H, Matsuo Y, Ueda G, et al.
Acquisition of gemcitabine resistance enhances angiogenesis via upregulation of IL‑8 production in pancreatic cancer.
Oncol Rep. 2019; 41(6):3508-3516 [PubMed] Related Publications
Gemcitabine (Gem) is widely used as chemotherapy for pancreatic cancer (PaCa), but its effect is not fully satisfactory. One of the reasons for this is the acquisition of Gem resistance (Gem‑R). To elucidate the mechanism of Gem‑R, two Gem‑R PaCa cell lines were established from AsPC‑1 and MIA PaCa‑2 cells. It was demonstrated that expression of interleukin‑8 (IL‑8) mRNA was significantly upregulated in Gem‑R PaCa cells by cDNA microarray and RT‑qPCR analyses. Increased IL‑8 secretion by Gem‑R cells was confirmed by cytokine array and enzyme‑linked immunosorbent assay. Moreover, we found that co‑culture with Gem‑R PaCa cells significantly enhanced tube formation of human umbilical vein endothelial cells, and treatment with an anti‑CXCR2 (main receptor for IL‑8) antibody significantly prevented this effect. We previously reported that a chemokine network centered on the IL‑8/CXCR2 axis plays an important role in PaCa angiogenesis, and suppression of this axis has an antitumor effect. Since acquisition of Gem‑R increased IL‑8 production and consequently increased tumor angiogenesis, the IL‑8/CXCR2 axis may be a potential novel therapeutic target for PaCa after acquiring Gem‑R.

Granata I, Troiano E, Sangiovanni M, Guarracino MR
Integration of transcriptomic data in a genome-scale metabolic model to investigate the link between obesity and breast cancer.
BMC Bioinformatics. 2019; 20(Suppl 4):162 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Obesity is a complex disorder associated with an increased risk of developing several comorbid chronic diseases, including postmenopausal breast cancer. Although many studies have investigated this issue, the link between body weight and either risk or poor outcome of breast cancer is still to characterize. Systems biology approaches, based on the integration of multiscale models and data from a wide variety of sources, are particularly suitable for investigating the underlying molecular mechanisms of complex diseases. In this scenario, GEnome-scale metabolic Models (GEMs) are a valuable tool, since they represent the metabolic structure of cells and provide a functional scaffold for simulating and quantifying metabolic fluxes in living organisms through constraint-based mathematical methods. The integration of omics data into the structural information described by GEMs allows to build more accurate descriptions of metabolic states.
RESULTS: In this work, we exploited gene expression data of postmenopausal breast cancer obese and lean patients to simulate a curated GEM of the human adipocyte, available in the Human Metabolic Atlas database. To this aim, we used a published algorithm which exploits a data-driven approach to overcome the limitation of defining a single objective function to simulate the model. The flux solutions were used to build condition-specific graphs to visualise and investigate the reaction networks and their properties. In particular, we performed a network topology differential analysis to search for pattern differences and identify the principal reactions associated with significant changes across the two conditions under study.
CONCLUSIONS: Metabolic network models represent an important source to study the metabolic phenotype of an organism in different conditions. Here we demonstrate the importance of exploiting Next Generation Sequencing data to perform condition-specific GEM analyses. In particular, we show that the qualitative and quantitative assessment of metabolic fluxes modulated by gene expression data provides a valuable method for investigating the mechanisms associated with the phenotype under study, and can foster our interpretation of biological phenomena.

Jahan R, Ganguly K, Smith LM, et al.
Trefoil factor(s) and CA19.9: A promising panel for early detection of pancreatic cancer.
EBioMedicine. 2019; 42:375-385 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Trefoil factors (TFF1, TFF2, and TFF3) are small secretory molecules that recently have gained significant attention in multiple studies as an integral component of pancreatic cancer (PC) subtype-specific gene signature. Here, we comprehensively investigated the diagnostic potential of all the member of trefoil family, i.e., TFF1, TFF2, and TFF3 in combination with CA19.9 for detection of PC.
METHODS: Trefoil factors (TFFs) gene expression was analyzed in publicly available cancer genome datasets, followed by assessment of their expression in genetically engineered spontaneous mouse model (GEM) of PC (KrasG12D; Pdx1-Cre (KC)) and in human tissue microarray consisting of normal pancreas adjacent to tumor (NAT), precursor lesions (PanIN), and various pathological grades of PC by immunohistochemistry (IHC). Serum TFFs and CA19.9 levels were evaluated via ELISA in comprehensive sample set (n = 362) comprised of independent training and validation sets each containing benign controls (BC), chronic pancreatitis (CP), and various stages of PC. Univariate and multivariate logistic regression and receiver operating characteristic curves (ROC) were used to examine their diagnostic potential both alone and in combination with CA19.9.
FINDINGS: The publicly available datasets and expression analysis revealed significant increased expression of TFF1, TFF2, and TFF3 in human PanINs and PC tissues. Assessment of KC mouse model also suggested upregulated expression of TFFs in PanIN lesions and early stage of PC. In serum analyses studies, TFF1 and TFF2 were significantly elevated in early stages of PC in comparison to benign and CP control group while significant elevation in TFF3 levels were observed in CP group with no further elevation in its level in early stage PC group. In receiver operating curve (ROC) analyses, combination of TFFs with CA19.9 emerged as promising panel for discriminating early stage of PC (EPC) from BC (AUC
INTERPRETATION: In silico, tissue and serum analyses validated significantly increased level of all TFFs in precursor lesions and early stages of PC. The combination of TFFs enhanced sensitivity and specificity of CA19.9 to discriminate early stage of PC from benign control and chronic pancreatitis groups.

Turanli B, Zhang C, Kim W, et al.
Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning.
EBioMedicine. 2019; 42:386-396 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genome-scale metabolic models (GEMs) offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time- and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment.
METHODS: In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with >1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions.
FINDINGS: We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line.
INTERPRETATION: Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.

Sun ZY, Jian YK, Zhu HY, Li B
lncRNAPVT1 targets miR-152 to enhance chemoresistance of osteosarcoma to gemcitabine through activating c-MET/PI3K/AKT pathway.
Pathol Res Pract. 2019; 215(3):555-563 [PubMed] Related Publications
BACKGROUND: LncRNA PVT1 has been reported to be involved in a variety of biological processes, including cell proliferation, cell differentiation and cancer progression. However, the mechanism by which LncRNA PVT1 contributes to chemoresistance of osteosarcoma cell, has not been fully elucidated.
METHODS: We first generatedLncRNA PVT1-overexpressed MG63 cells and LncRNA PVT1 knockdown MG63/DOX cells. Then, we examined the effect of LncRNA PVT1 on cell viability and colony formation ability by MTT assay and soft agar assay, respectively. In addition, we performed flow cytometry analysis to detect apoptosis induced by GEM. Dual luciferase reporter assay and RIP were used to confirmed the interaction between LncRNA PVT1 and miR-152. Finally, we determined protein level of c-MET, p-PI3K, and p-AKT by westernblot.
RESULTS: LncRNA PVT1 overexpression promoted cell proliferation and exhibited the anti-apoptotic property in LncRNA PVT1-overexpressing MG63 cells treated with gemcitabine. While, LncRNA PVT1-depleted MG63/DOX cells treated with gemcitabine exhibited significant lower survival rate and high percentage of apoptosis. Next, we found that LncRNA PVT1 could target and downregulated the level of miR-152. Interestingly, miR-152 greatly rescued the biological outcomes of LncRNA PVT1 not only in MG63 but also in MG63/DOX cells. We observed that LncRNA PVT1 markedly induced PI3K/AKT pathway activation, which was abolished by miR-152 mimics overexpression. Finally, c-MET inhibitor was used to confirm the essential role of c-MET in LncRNA PVT1 and miR-152-regulated PI3K/AKT signaling.
CONCLUSION: We showed thatlncRNA PVT1 played a contributory role in chemoresistance of osteosarcoma cells through c-MET/PI3K/AKT pathway activation, which was largely dependent on miR-152. Our findings advance our understanding of how lncRNA PVT1 promotes chemoresistance of osteosarcoma cells and facilitate development of novel strategies for treating osteosarcoma.

Sakai Y, Miyazawa M, Komura T, et al.
Distinct chemotherapy-associated anti-cancer immunity by myeloid cells inhibition in murine pancreatic cancer models.
Cancer Sci. 2019; 110(3):903-912 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with an extremely poor prognosis. Chemotherapy, such as gemcitabine (GEM), is the only treatment for PDAC patients who are not suitable for radical surgical treatment; however, its anti-tumor efficacy is limited. In this study, we investigated the host immune system response in murine PDAC models undergoing GEM treatment. We found that PDAC tumor tissues were infiltrated with a substantial number of Gr-1+ myeloid cells and had relatively small numbers of CD4+ and CD8+ cells. In addition, there were increased numbers of myeloid cells expressing CD11b+ and Gr-1+ in peripheral blood. When mice with PDAC tumors in the intraperitoneal cavity or liver were treated with GEM, numbers of myeloid cells in tumor tissues and in peripheral blood decreased. In contrast, numbers of CD4+ or CD8+ cells increased. In peripheral blood, the numbers of CD8+ cells expressing interferon-gamma (IFN-γ) were higher in GEM-treated mice than in untreated mice. In addition, GEM treatment in combination with myeloid cell depletion further prolonged the survival of PDAC mice. The gene expression profile of peripheral blood in myeloid cell-depleted PDAC mice treated with GEM showed biological processes related to anti-cancer immunity, such as natural killer cell-mediated cytotoxicity, type I IFN signaling, and co-stimulatory signaling for T cell activation. Thus, in PDAC murine models, GEM treatment was associated with an immune response consistent with an anti-cancer effect, and depletion of myeloid-lineage cells played an important role in enhancing anti-cancer immunity associated with GEM treatment.

Diab M, Azmi A, Mohammad R, Philip PA
Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges.
Expert Opin Pharmacother. 2019; 20(5):535-546 [PubMed] Related Publications
INTRODUCTION: Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease.
AREAS COVERED: This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease.
EXPERT OPINION: Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemcitabine (GEM) and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). PDAC has a number of genetic mutations that may explain its biological behavior, such as KRAS, p53 and CDK2NA, which occur in more than 90% of cases. Unfortunately, to this day, a specific targeting agent to any of those frequent gene mutations is lacking. Emerging areas of targeted therapies include the DNA repair, stroma, metabolism, and stem cells. Immunotherapy with either vaccines or immune checkpoint inhibitors has not produced any significant improvements in outcome of PDAC. Incorporating different approaches in therapy, including conventional, immunological, and others, is key in offering patients with the best possible care.

Aygun N, Altungoz O
MYCN is amplified during S phase, and c‑myb is involved in controlling MYCN expression and amplification in MYCN‑amplified neuroblastoma cell lines.
Mol Med Rep. 2019; 19(1):345-361 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma derived from primitive sympathetic neural precursors is a common type of solid tumor in infants. MYCN proto‑oncogene bHLH transcription factor (MYCN) amplification and 1p36 deletion are important factors associated with the poor prognosis of neuroblastoma. Expression levels of MYCN and c‑MYB proto‑oncogene transcription factor (c‑myb) decline during the differentiation of neuroblastoma cells; E2F transcription factor 1 (E2F1) activates the MYCN promoter. However, the underlying mechanism of MYCN overexpression and amplification requires further investigation. In the present study, potential c‑Myb target genes, and the effect of c‑myb RNA interference (RNAi) on MYCN expression and amplification were investigated in MYCN‑amplified neuroblastoma cell lines. The mRNA expression levels and MYCN gene copy number in five neuroblastoma cell lines were determined by quantitative polymerase chain reaction. In addition, variations in potential target gene expression and MYCN gene copy number between pre‑ and post‑c‑myb RNAi treatment groups in MYCN‑amplified Kelly, IMR32, SIMA and MHH‑NB‑11 cell lines, normalized to those of non‑MYCN‑amplified SH‑SY5Y, were examined. To determine the associations between gene expression levels and chromosomal aberrations, MYCN amplification and 1p36 alterations in interphases/metaphases were analyzed using fluorescence in situ hybridization. Statistical analyses revealed correlations between 1p36 alterations and the expression of c‑myb, MYB proto‑oncogene like 2 (B‑myb) and cyclin dependent kinase inhibitor 1A (p21). Additionally, the results of the present study also demonstrated that c‑myb may be associated with E2F1 and L3MBTL1 histone methyl‑lysine binding protein (L3MBTL1) expression, and that E2F1 may contribute to MYCN, B‑myb, p21 and chromatin licensing and DNA replication factor 1 (hCdt1) expression, but to the repression of geminin (GMNN). On c‑myb RNAi treatment, L3MBTL1 expression was silenced, while GMNN was upregulated, indicating G2/M arrest. In addition, MYCN gene copy number increased following treatment with c‑myb RNAi. Notably, the present study also reported a 43.545% sequence identity between upstream of MYCN and Drosophila melanogaster amplification control element 3, suggesting that expression and/or amplification mechanisms of developmentally‑regulated genes may be evolutionarily conserved. In conclusion, c‑myb may be associated with regulating MYCN expression and amplification. c‑myb, B‑myb and p21 may also serve a role against chromosome 1p aberrations. Together, it was concluded that MYCN gene is amplified during S phase, potentially via a replication‑based mechanism.

Feng M, Xiong G, Cao Z, et al.
LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.
J Exp Clin Cancer Res. 2018; 37(1):274 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Reprogrammed energy metabolism has become an emerging hallmark of cancer in recent years. Transporters have been reported to be amino acid sensors involved in controlling mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), encoded by the SLC7A8 gene, is a Na
METHODS: The effects of LAT2 on biological behaviors were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated.
RESULTS: We demonstrated that LAT2 emerged as an oncogenic protein and could decrease the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. The results of a survival analysis indicated that high expression levels of both LAT2 and LDHB predicted a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, we found that gemcitabine combined with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, we demonstrated that LAT2 could regulate two glutamine-dependent positive feedback loops (the LAT2/p-mTOR
CONCLUSION: Taken together, our data reveal that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease GEM sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.

Hu W, Liu Q, Pan J, Sui Z
MiR-373-3p enhances the chemosensitivity of gemcitabine through cell cycle pathway by targeting CCND2 in pancreatic carcinoma cells.
Biomed Pharmacother. 2018; 105:887-898 [PubMed] Related Publications
OBJECTIVE: This study aimed to detect the expression of miR-373-3p and CCND2 in gemcitabine-resistance pancreatic carcinoma (PC) cells, investigate the relationship between miR-373-3p and CCND2, and explore their effects on PC propagation, migration, invasion and apoptosis.
METHODS: R software was applied for analyzing differentially expressed genes (DEGs) in cell samples. The potential biological pathway was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, based on R software. The gemcitabine-resistance PC cells were screened out using MTT assay, and they were applied in the next experiments. MiR-373-3p and CCND2 expression in GEM-PANC-1 cells were measured by qRT-PCR. After transfection, the expression of CCND2 protein was examined via western blot assay. Cells viability and apoptosis were confirmed by MTT proliferation assay and Flow cytometry, whereas cells migration and invasion were analyzed by transwell assay. The targeting relationship between miR-373-3p and CCND2 was identified by dual-luciferase reporter assay.
RESULTS: MiR-373-3p was found to be low expressed in GEM-PANC-1 cells while CCND2 was highly expressed in GEM-PANC-1 cells. MiR-373-3p negatively regulated CCND2 expression through KEGG_Cell_Cycle_Signaling_Pathway. The targeted relationship between miR-373-3p and CCND2 could be verified using dual luciferase reporter assay. MTT proliferation assay, transwell assay and Annexin V assay demonstrated that miR-373-3p suppressed GEM-PANC-1 cells propagation and invasion and promoted cell apoptosis, while CCND2 showed totally reverse effects compared with miR-373-3p. All the results suggested that miR-373-3p could enhance the chemosensitivity of GEM-PANC-1 cells by regulating CCND2.
CONCLUSION: MiR-373-3p inhibited cell propagation, migration and invasion and boosted apoptosis in gemcitabine resistance pancreatic carcinoma cells by targeting CCND2.

Kannagi R, Cai BH, Huang HC, et al.
Gangliosides and Tumors.
Methods Mol Biol. 2018; 1804:143-171 [PubMed] Related Publications
Tumor-associated gangliosides play important roles in regulation of signal transduction induced by growth-factor receptors including EGFR, FGFR, HGF and PDGFR in a specific microdomain called glycosynapse in the cancer cell membranes, and in interaction with glycan recognition molecules involved in cell adhesion and immune regulation including selectins and siglecs. As the genes involved in the synthesis and degradation of tumor-associated gangliosides were identified, biological functions became clearer from the experimental results employing forced overexpression and/or knockdown/knockout of the genes. Studies on the regulatory mechanisms for their expression also achieved great advancements. Epigenetic silencing of glycan-related genes is a dominant mechanism in glycan alteration at early stages of carcinogenesis. Development of hypoxia resistance involving activation of a transcription factor HIF, and acquisition of cancer stem cell-like characteristics through epithelial-mesenchymal transition are important mechanisms for glycan modulations in the later stages of cancer progression. In the initial stages of studies, the gangliosides which specifically appear in cancers attracted attention under the name of tumor-associated gangliosides. However, it became apparent that not only the cancer-associated gangliosides but also the normal gangliosides present in nonmalignant cells and tissues perform important biological functions, and some of them tend to disappear in cancer cells resulting in the loss of the physiological functions, and this sometimes facilitates progression of cancers.

Hu BD, Guo J, Ye YZ, et al.
Specific inhibitor of Notch‑3 enhances the sensitivity of NSCLC cells to gemcitabine.
Oncol Rep. 2018; 40(1):155-164 [PubMed] Free Access to Full Article Related Publications
Notch‑3 is a receptor of the Notch signaling pathway and plays an important role in regulating self‑renewal, differentiation and apoptosis in cancer cells. Overexpression of Notch‑3 has been proved to be associated with resistance to gemcitabine (GEM) and poor patient prognosis for various malignant tumors. In the present study, two non‑small cell lung cancer (NSCLC) cell lines, H1299 and A549, were induced with GEM for two months and then were treated with various concentrations of a Notch signaling blocker, N‑[N‑(3,5‑difluorophenacetyl)‑L‑alanyl]‑S‑phenylglycine t‑butyl ester (DAPT), with the goal of reducing expression of Notch intracellular domain 3 (NICD3). Both cell lines were subsequently treated with either DAPT or DAPT combined with GEM and then viability, apoptosis, colony formation and cell count assays were performed. DAPT treatment effectively downregulated the expression of NICD3 in both cell lines. DAPT combined with GEM also significantly reduced the percentage of viable cells in both cell lines, while increasing the percentage of apoptotic cells, compared with GEM alone. In the clonogenicity assays, the combination of DAPT and GEM led to a decrease in clone numbers and significantly greater inhibition of the H1299 and A549 cells compared to treatment with DAPT or GEM alone. Meanwhile, levels of the apoptosis‑related proteins, Bcl‑2 and Bax, were found to be affected by the various treatments. Thus Notch‑3 appears to be a promising target for gene therapy and DAPT is able to mediate a strong antitumor effect in NSCLC cells that overexpress Notch‑3. Further studies of a combined treatment regimen with DAPT and GEM are warranted and may provide greater efficacy and safety in the treatment of NSCLC patients.

Xu C, Yu Y, Ding F
Microarray analysis of circular RNA expression profiles associated with gemcitabine resistance in pancreatic cancer cells.
Oncol Rep. 2018; 40(1):395-404 [PubMed] Related Publications
Pancreatic cancer (PC) is one of the most malignant tumors of the digestive system due to its rapid progression, metastasis and resistance to chemotherapy. Gemcitabine (GEM) chemotherapy is the first‑choice treatment for advanced PC. However, the effect of GEM‑based chemotherapy on PC is limited due to the development of chemoresistance, and the molecular mechanisms underlying this resistance have yet to be investigated. Circular RNAs (circRNAs), which can function as microRNA sponges, have been found to be involved in the development of several types of cancer. However, research on circRNAs in PC drug resistance is limited. In the present study, the GEM‑resistant PC cell line, SWl990/GZ, was successfully established by treating parental SWl990 cells in vitro with increasing concentrations of GEM in culture medium intermittently for 10 months. By analyzing the expression profiles of circRNAs in microarray between SWl990/GZ and parental SW1990 cells, we identified 26 upregulated and 55 downregulated circRNAs (fold change ≥2 and P<0.05) among 12,866 detected circRNAs in SWl990/GZ compared with SW1990 cells. Furthermore, the changes in the expression of six representative circRNAs was validated by reverse transcription‑quantitative PCR. In addition, Kyoto Encyclopedia of Genes and Genomes pathway analysis and Gene Ontology analysis were performed. These analyses revealed that the dysregulated circRNAs regulated several cancer‑related pathways, such as the mitogen‑activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and may be involved in the biological process of the regulation of chemoresistance, including nucleic acid metabolic process and cellular response to stress. The present study undertook a comprehensive expression analysis and revealed the functional profiles of differentially expressed circRNAs associated with GEM‑resistance in PC, thereby indicating the possible participation of these dysregulated circRNAs in the development of chemoresistance and providing novel potential therapeutic targets for PC.

Wang JH, Lee EJ, Ji M, Park SM
HDAC inhibitors, trichostatin A and valproic acid, increase E‑cadherin and vimentin expression but inhibit migration and invasion of cholangiocarcinoma cells.
Oncol Rep. 2018; 40(1):346-354 [PubMed] Related Publications
The effects of histone deacetylase (HDAC) inhibitors on epithelial-mesenchymal transition (EMT) differ in various cancers. E‑cadherin is a cell‑to‑cell adhesion protein, whereas accumulation of vimentin is related to the development of the spindle shape of the mesenchymal cell phenotype. We investigated the EMT phenotypes of human cholangiocellular carcinoma HuCC‑T1, JCK and SNU‑1079 cell lines. To this end, we measured the expression of E‑cadherin or zonula occludens (ZO)‑1 and vimentin, epithelial and mesenchymal cell markers, respectively, using real‑time reverse transcription‑polymerase chain reaction, western blotting, and immunofluorescence microscopy following treatment with trichostatin A (TSA, 200 nM) or valproic acid (VPA, 0.5 mM) with or without gemcitabine (GEM, 50 nM) for 24 h. In addition, we performed cell morphology, migration, and invasion assays. HuCC‑T1 cells changed from spindle‑ to rectangular‑shaped after co‑treatment with GEM and TSA or VPA. Furthermore, cells co‑treated with GEM and TSA or VPA exhibited protein levels of E‑cadherin or ZO‑1 that were higher than those in cells treated with GEM alone, indicating stronger inhibition of EMT. However, vimentin expression was also increased. Confocal microscopy revealed enhanced expression of E‑cadherin or ZO‑1 and vimentin in all three cell lines. Migration and invasion were inhibited in HuCC‑T1 cells co‑treated with GEM and TSA or VPA, compared to those treated with GEM alone. In conclusion, co‑treatment of cholangiocarcinoma cells with TSA or VPA and GEM suppressed EMT with tolerable cytotoxicity. However, the HDAC inhibitors augmented both E‑cadherin and vimentin expression and their effects varied in different cholangiocarcinoma cell lines. Therefore, the clinical use of HDAC inhibitors in biliary cancer should be considered cautiously.

Kawano M, Kaino S, Amano S, et al.
Heat Shock Protein 27 Expression in EUS-FNA Samples Can Predict Gemcitabine Sensitivity in Pancreatic Cancer.
In Vivo. 2018 May-Jun; 32(3):637-642 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: Gemcitabine (GEM) sensitivity can help select the appropriate treatment for pancreatic cancer. We examined the association between HSP27 expression and GEM sensitivity.
MATERIALS AND METHODS: A total of 19 patients with unresectable pancreatic cancer who underwent endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) were enrolled and treated with GEM alone. We measured the expression of heat shock protein 27 (HSP27) and phosphorylated HSP27(p-HSP27) in EUS-FNA samples and evaluated the effects of GEM treatment.
RESULTS: The rate of GEM resistance was significantly higher in patients who showed overexpression of p-HSP27 (p<0.05). When we set the cut-off p-HSP27 (Ser82) detection rate at 51.6%, the group with a detection rate of >51.6% showed a significantly lower survival rate, and GEM was administered for a shorter period of time (p<0.05).
CONCLUSION: It was suggested that the HSP27 expression in EUS-FNA samples was useful for predicting GEM sensitivity.

An Q, Zhou L, Xu N
Long noncoding RNA FOXD2-AS1 accelerates the gemcitabine-resistance of bladder cancer by sponging miR-143.
Biomed Pharmacother. 2018; 103:415-420 [PubMed] Related Publications
Increasing evidences have proved that long noncoding RNAs (lncRNAs) modulate the tumorigenesis of bladder cancer involved in multiple pathophysiological processes. In the study, we investigate the role of lncRNA FOXD2-AS1 in the gemcitabine (GEM) resistant bladder cancer and explore its potential mechanism. Results showed that lncRNA FOXD2-AS1 was high-expressed in gemcitabine-resistant bladder cancer cells. In vitro experiments, FOXD2-AS1 knockdown suppressed the 50% inhibitive concentration (IC50) of gemcitabine, drug-resistance related genes (MDR1, MRP2, LRP1) expression, invasion and ABCC3 protein expression in gemcitabine-resistant bladder cancer cells (T24/GEM, 5637/GEM). In vivo of xenograft assay, FOXD2-AS1 knockdown inhibited the tumor growth of bladder cancer cells. Bioinformatics program and validation experiments confirmed that FOXD2-AS1 positively regulated ABCC3 protein through targeting miR-143, acting as a competing endogenous RNA (ceRNA). In summary, our results revealed the vital roles of FOXD2-AS1/miR-143/ABCC3 axis in gemcitabine resistance of bladder cancer cells, providing a novel therapeutic strategy for bladder cancer.

Hou W, Ji Z
Generation of autochthonous mouse models of clear cell renal cell carcinoma: mouse models of renal cell carcinoma.
Exp Mol Med. 2018; 50(4):30 [PubMed] Free Access to Full Article Related Publications
Renal cell carcinoma (RCC) is one of the 10 most common cancers worldwide, and to date, a strong systemic therapy has not been developed to treat RCC, even with the remarkable modern advances in molecular medicine mostly due to our incomplete understanding of its tumorigenesis. There is a dire unmet need to understand the etiology and progression of RCC, especially the most common subtype, clear cell RCC (ccRCC), and to develop new treatments for RCC. Genetically engineered mouse (GEM) models are able to mimic the initiation, progression, and metastasis of cancer, thus providing valuable insights into tumorigenesis and serving as perfect preclinical platforms for drug testing and biomarker discovery. Despite substantial advances in the molecular investigation of ccRCC and monumental efforts that have been performed to try to establish autochthonous animal models of ccRCC, this goal has not been achieved until recently. Here we present a review of the most exciting progress relevant to GEM models of ccRCC.

Sang M, Nakamura M, Ogata T, et al.
Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53‑mutated pancreatic cancer MiaPaCa‑2 spheres.
Oncol Rep. 2018; 39(6):2749-2758 [PubMed] Related Publications
Recently, it has been well‑recognized that the response toward anticancer drugs differs between two‑ and three‑dimensional (2D and 3D) in vitro cancer cell growth models. In the present study, we have demonstrated that, similar to the conventional 2D monolayer culture systems which often lack in vivo physiological insights, RUNX2 gene silencing increases the gemcitabine (GEM) sensitivity of the 3D spheres generated from p53‑mutated pancreatic cancer MiaPaCa‑2 cells. According to our results, MiaPaCa‑2 cells, but not p53‑wild‑type pancreatic cancer SW1990 cells efficiently formed sphere structures in serum‑free sphere‑forming medium. Although GEM treatment caused a marked induction of TAp73/TAp63 in MiaPaCa‑2 spheres accompanied by the transcriptional activation of p53 family‑target genes such as p21WAF1 and NOXA, only 20% of cells underwent cell death. Under these experimental conditions, mutant p53 expression level was increased in response to GEM and RUNX2 remained unchanged at the protein level regardless of GEM exposure, which may suppress the pro‑apoptotic activity of TAp73/TAp63. Notably, RUNX2 gene silencing markedly augmented GEM‑mediated cell death of MiaPaCa‑2 spheres compared to that of non‑depleted ones. Expression analyses revealed that forced depletion of RUNX2 further stimulated GEM‑induced upregulation of TAp63 as well as its downstream target genes such as p21WAF1 and NOXA. In summary, our observations strongly indicated that, similarly to 2D monolayer culture, RUNX2 gene silencing increased GEM sensitivity of MiaPaCa‑2 spheres and highlighted the therapeutic potential of RUNX2 in pancreatic cancer with p53 mutation.

Han L, Jiang J, Ma Q, et al.
The inhibition of heme oxygenase-1 enhances the chemosensitivity and suppresses the proliferation of pancreatic cancer cells through the SHH signaling pathway.
Int J Oncol. 2018; 52(6):2101-2109 [PubMed] Related Publications
Pancreatic cancer (PC) is a type of cancer associated with a high fatality rate due to a poor prognosis and resistance to treatment. Heme oxygenase-1 (HO-1) is significantly overexpressed in a number of types of cancer and seems to play an important role in cancer progression. In this study, we examined the potential effects of HO-1 on PC cell proliferation and sensivity to gemcitabine (Gem). Furthermore, the role of the sonic hedgehog (SHH) signaling pathway in the regulatory effects of HO-1 on PC progression were examined. For this purpose, the expression of HO-1 was examined in cultured PC cells by real-time PCR, western blot analysis and immunofluorescence. Transfection with small interfering RNA against HO-1 or an overexpression plasmid were used to regulate the expression of HO-1 in the MIA PaCa-2 and PANC-1 cell lines. Cell proliferation was examined by MTT assays in response to the different treatments. The results revealed that HO-1 expression differed significantly in the different PC cells. The overexpression of HO-1 induced PC cell proliferation and the inhibition of HO-1 decreased the cell proliferative ability. Furthermore, HO-1 activated the SHH signaling pathway in the PC cells. In addition, the SHH signaling pathway was found to play a role in HO-1-induced PC cell proliferation. The inhibition of HO-1 enhanced the responsiveness of PC cells to Gem and Gem was found to regulate the expression of HO-1 and the activation of the SHH pathway. On the whole, our findings indicate that HO-1 overexpression in PC cells may be responsible for the increased cell proliferation and the resistance to anticancer therapy. Furthermore, the SHH signaling pathway, the activation of which was initiated by HO-1, may be one of the endogenous mechanisms in this process. Our data shed light into the association between HO-1 and SHH in PC cells, and may aid in the development of novel therapeutic targets for the treatment of patients with PC.

Ahmed FE, Ahmed NC, Gouda MM, et al.
RT-qPCR for Fecal Mature MicroRNA Quantification and Validation.
Methods Mol Biol. 2018; 1765:203-215 [PubMed] Related Publications
By routinely and systematically being able to perform quantitative stem-loop reverse transcriptase (RT) followed by TaqMan® minor-groove binding (MGB) probe, real-time quantitative PCR analysis on exfoliated enriched colonocytes in stool, using human (Homo sapiens, hsa) micro(mi)RNAs to monitor changes of their expression at various stages of colorectal (CRC) progression, this method allows for the reliable and quantitative diagnostic screening of colon cancer (CC). Although the expression of some miRNA genes tested in tissue shows less variability in normal or cancerous patients than in stool, the noninvasive stool by itself is well suited for CC screening. An miRNA approach using stool promises to offer more sensitivity and specificity than currently used genomic, methylomic, or proteomic methods for CC screening.To present an application of employing miRNAs as diagnostic markers for CC screening, we carried out global microarray expression studies on stool colonocytes isolated by paramagnetic beads, using Affymetrix GeneChip miRNA 3.0 Array, to select a panel of miRNAs for subsequent focused semiquantitative PCR analysis studies. We then conducted a stem-loop RT-TaqMan® MGB probes, followed by a modified real-time qPCR expression study on 20 selected miRNAs for subsequent validation of the extracted immunocaptured total small RNA isolated from stool colonocytes. Results showed 12 miRNAs (miR-7, miR-17, miR-20a, miR-21, miR-92a, miR-96, miR-106a, miR-134, miR-183, miR-196a, miR-199a-3p, and miR214) to have an increased expression in stool of CC patients, and that later TNM stages exhibited more increased expressions than adenomas, while 8 miRNAs (miR-9, miR-29b, miR-127-5p, miR-138, miR-143, miR-146a, miR-222, and miR-938) showed decreased expressions in stool of CC patients, which becomes more pronounced as the cancer progresses from early to late TNM stages (0-IV).

Zhu J, Chen Y, Ji Y, et al.
Gemcitabine induces apoptosis and autophagy via the AMPK/mTOR signaling pathway in pancreatic cancer cells.
Biotechnol Appl Biochem. 2018; 65(5):665-671 [PubMed] Related Publications
Gemcitabine (GEM)-based chemotherapy is a commonly used treatment for pancreatic cancer. However, acquired drug resistance, a major problem in pancreatic cancer treatment, causes a reduction in the survival rate of patients with cancer. In this study, we attempted to reveal the molecular mechanism of GEM resistance. Our data showed that GEM treatment inhibits cell growth, induces apoptosis, and activates autophagy via the AMP-activated protein kinase (AMPK) pathway. The combination of GEM treatment and AMPK knockdown resulted in a dramatic increase of apoptosis and inhibition of autophagy. Additionally, inhibition of mammalian target of Rapamycin induced autophagy. Our findings show the potential therapeutic implications of the combined treatment with GEM and AMPK inhibitors for pancreatic cancer.

Lin L, Fan Y, Gao F, et al.
UTMD-Promoted Co-Delivery of Gemcitabine and miR-21 Inhibitor by Dendrimer-Entrapped Gold Nanoparticles for Pancreatic Cancer Therapy.
Theranostics. 2018; 8(7):1923-1939 [PubMed] Free Access to Full Article Related Publications
Conventional chemotherapy of pancreatic cancer (PaCa) suffers the problems of low drug permeability and inherent or acquired drug resistance. Development of new strategies for enhanced therapy still remains a great challenge. Herein, we report a new ultrasound-targeted microbubble destruction (UTMD)-promoted delivery system based on dendrimer-entrapped gold nanoparticles (Au DENPs) for co-delivery of gemcitabine (Gem) and miR-21 inhibitor (miR-21i).

Zhao X, Wang X, Sun W, et al.
Precision design of nanomedicines to restore gemcitabine chemosensitivity for personalized pancreatic ductal adenocarcinoma treatment.
Biomaterials. 2018; 158:44-55 [PubMed] Related Publications
Low chemosensitivity considerably restricts the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer treatment. Using immunohistochemical evaluation, we investigated that decreased expression of human equilibrative nucleoside transporter-1 (hENT1, which is the major GEM transporter across cell membranes) and increased expression of ribonucleotide reductase subunit 2 (RRM2, which decreases the cytotoxicity of GEM) was associated with low GEM chemosensitivity. To solve these problems, we employed a nanomedicine-based formulation of cationic liposomes for co-delivery of GEM along with siRNA targeting RRM2. Due to the specific endocytic uptake mechanism of nanocarriers and gene-silencing effect of RRM2 siRNA, this nanomedicine formulation significantly increased GEM chemosensitivity in tumor models of genetically engineered Panc1 cells with low hENT1 or high RRM2 expression. Moreover, in a series of patient-derived cancer cells, we demonstrated that the therapeutic benefits of the nanomedicine formulations were associated with the expression levels of hENT1 and RRM2. In summary, we found that the essential factors of GEM chemosensitivity were the expression levels of hENT1 and RRM2, and synthesized nanoformulations can overcome these problems. This unique design of nanomedicine not only provides a universal platform to enhance chemosensitivity but also contributes to the precision design and personalized treatment in nanomedicine.

Arbi M, Pefani DE, Taraviras S, Lygerou Z
Controlling centriole numbers: Geminin family members as master regulators of centriole amplification and multiciliogenesis.
Chromosoma. 2018; 127(2):151-174 [PubMed] Related Publications
To ensure that the genetic material is accurately passed down to daughter cells during mitosis, dividing cells must duplicate their chromosomes and centrosomes once and only once per cell cycle. The same key steps-licensing, duplication, and segregation-control both the chromosome and the centrosome cycle, which must occur in concert to safeguard genome integrity. Aberrations in genome content or centrosome numbers lead to genomic instability and are linked to tumorigenesis. Such aberrations, however, can also be part of the normal life cycle of specific cell types. Multiciliated cells best exemplify the deviation from a normal centrosome cycle. They are post-mitotic cells which massively amplify their centrioles, bypassing the rule for once-per-cell-cycle centriole duplication. Hundreds of centrioles dock to the apical cell surface and generate motile cilia, whose concerted movement ensures fluid flow across epithelia. The early steps that control the generation of multiciliated cells have lately started to be elucidated. Geminin and the vertebrate-specific GemC1 and McIdas are distantly related coiled-coil proteins, initially identified as cell cycle regulators associated with the chromosome cycle. Geminin is required to ensure once-per-cell-cycle genome replication, while McIdas and GemC1 bind to Geminin and are implicated in DNA replication control. Recent findings highlight Geminin family members as early regulators of multiciliogenesis. GemC1 and McIdas specify the multiciliate cell fate by forming complexes with the E2F4/5 transcription factors to switch on a gene expression program leading to centriole amplification and cilia formation. Positive and negative interactions among Geminin family members may link cell cycle control to centriole amplification and multiciliogenesis, acting close to the point of transition from proliferation to differentiation. We review key steps of centrosome duplication and amplification, present the role of Geminin family members in the centrosome and chromosome cycle, and discuss links with disease.

Ma Z, Xue X
Differentially expressed proteins in the human esophageal cancer cell line Eca‑109, in the presence and absence of gemcitabine.
Mol Med Rep. 2018; 17(1):1873-1878 [PubMed] Related Publications
The present study aimed to screen and study the roles of differentially expressed proteins in the human esophageal cancer cell line Eca‑109, in the presence and absence of gemcitabine (GEM). The 3‑(4,5)‑dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) method was used to assay the vitality of the Eca‑109 cells following treatment with GEM (1‑16 µg/ml). The cell apoptosis was measured by using fluorescence activated cell sorting. The proteins in the treated Eca‑109 cells were extracted, validated, and assayed via two‑dimensional gel electrophoresis combined with matrix‑assisted laser desorption/ionization time of flight mass spectrometry (MALDI‑TOF‑MS). The differentially expressed proteins were then determined by western blotting. Furthermore, alterations in mitochondrial ultrastructure of the treated cells were observed under a transmission electron microscope. GEM significantly inhibited the growth of the Eca‑109 cells in a concentration‑ and time‑dependent manner, and the 50% inhibition concentration (IC50) value was 3.87 µg/ml. The MALDI‑TOF‑MS analysis revealed that there were three differentially expressed proteins following the GEM treatment, compared with the control. The differential proteins were verified to be B cell lymphoma‑2 associated X, apoptosis regulator (Bax)‑α, apoptosis‑associated speck‑like protein containing a CARD (ASC) and myeloid cell leukemia sequence (Mcl)‑1. Western blotting revealed that the expression levels of ASC and Bax‑α proteins in the treated cancer cells were significantly upregulated, whereas the Mcl‑1 protein expression was markedly downregulated compared with the control. Furthermore, the GEM treatment destroyed the mitochondrial ultrastructure of the cancer cells, leaving swelled mitochondria, a fading matrix and destroyed the mitochondrial cristae. GEM significantly inhibits the growth and promotes apoptosis of the Eca‑109 cells, due to the alterations in the expression levels of the differential proteins, including ASC, Mcl‑1 and Bax‑α.

Ryu JY, Kim HU, Lee SY
Framework and resource for more than 11,000 gene-transcript-protein-reaction associations in human metabolism.
Proc Natl Acad Sci U S A. 2017; 114(45):E9740-E9749 [PubMed] Free Access to Full Article Related Publications
Alternative splicing plays important roles in generating different transcripts from one gene, and consequently various protein isoforms. However, there has been no systematic approach that facilitates characterizing functional roles of protein isoforms in the context of the entire human metabolism. Here, we present a systematic framework for the generation of gene-transcript-protein-reaction associations (GeTPRA) in the human metabolism. The framework in this study generated 11,415 GeTPRA corresponding to 1,106 metabolic genes for both principal and nonprincipal transcripts (PTs and NPTs) of metabolic genes. The framework further evaluates GeTPRA, using a human genome-scale metabolic model (GEM) that is biochemically consistent and transcript-level data compatible, and subsequently updates the human GEM. A generic human GEM, Recon 2M.1, was developed for this purpose, and subsequently updated to Recon 2M.2 through the framework. Both PTs and NPTs of metabolic genes were considered in the framework based on prior analyses of 446 personal RNA-Seq data and 1,784 personal GEMs reconstructed using Recon 2M.1. The framework and the GeTPRA will contribute to better understanding human metabolism at the systems level and enable further medical applications.

Derks JL, Leblay N, Thunnissen E, et al.
Molecular Subtypes of Pulmonary Large-cell Neuroendocrine Carcinoma Predict Chemotherapy Treatment Outcome.
Clin Cancer Res. 2018; 24(1):33-42 [PubMed] Related Publications

Kawamura D, Takemoto Y, Nishimoto A, et al.
Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells.
Oncol Rep. 2017; 38(5):3238-3244 [PubMed] Related Publications
Although gemcitabine (GEM) is frequently used in the treatment of pancreatic cancer, the effects are limited. To increase the inhibitory effect of GEM, the identification of a molecular target is needed. Recent studies have revealed that doublecortin-like kinase 1 (Dclk1) positively regulates tumor growth, invasion, metastasis, factors related to epithelial-mesenchymal transition (EMT), pluripotency, angiogenesis, and anti-apoptosis in pancreatic cancer cells. Therefore, Dclk1 is a potential therapeutic target for pancreatic cancer. However, the Dclk1-signaling pathway including its substrate proteins remains to be elucidated. To identify the candidate substrate proteins phosphorylated by Dclk1, we performed a cancer-related phosphorylated protein microarray using Dclk1-inhibited MIA Paca2 cells. Expression levels of phosphorylated cdc25A (p-cdc25A) and phosphorylated Chk1 (p-Chk1), belonging to the ATR pathway, were decreased by treatment with Dclk1 inhibitor LRRK2-IN-1 (LRRK), indicating Dclk1 involvement in the ATR pathway. Consistent with this finding, the GEM-induced p-Chk1 expression was significantly decreased by treatment with LRRK. Notably, combined treatment with GEM and LRRK allowed cell cycle progression without arresting at S phase, while individual treatment with GEM induced cell cycle arrest at S phase. In addition, combined treatment with GEM and LRRK increased the number of γ-H2AX-positive cells compared with that upon individual treatments. Moreover, LRRK alone, and combined treatment with GEM and LRRK, induced caspase-3 activation and PARP1 cleavage, in contrast to treatment with GEM alone. Finally, combined treatment with GEM and LRRK significantly reduced cell survival compared to individual treatment with GEM. These results indicate that Dclk1 inhibition in combination with GEM treatment offers a novel approach to treat pancreatic cancer cells.

Raap M, Gronewold M, Christgen H, et al.
Lobular carcinoma in situ and invasive lobular breast cancer are characterized by enhanced expression of transcription factor AP-2β.
Lab Invest. 2018; 98(1):117-129 [PubMed] Related Publications
Transcription factor AP-2β (TFAP2B) regulates embryonic organ development and is overexpressed in alveolar rhabdomyosarcoma, a rare childhood malignancy. Gene expression profiling has implicated AP-2β in breast cancer (BC). This study characterizes AP-2β expression in the mammary gland and in BC. AP-2β protein expression was assessed in the normal mammary gland epithelium, in various reactive, metaplastic and pre-invasive neoplastic lesions and in two clinical BC cohorts comprising >2000 patients. BCs from various genetically engineered mouse (GEM) models were also evaluated. Human BC cell lines served as functional models to study siRNA-mediated inhibition of AP-2β. The normal mammary gland epithelium showed scattered AP-2β-positive cells in the luminal cell layer. Various reactive and pre-invasive neoplastic lesions, including apocrine metaplasia, usual ductal hyperplasia and lobular carcinoma in situ (LCIS) showed enhanced AP-2β expression. Cases of ductal carcinoma in situ (DCIS) were more often AP-2β-negative (P<0.001). In invasive BC cohorts, AP-2β-positivity was associated with the lobular BC subtype (P<0.001), loss of E-cadherin (P<0.001), a positive estrogen receptor (ER) status (P<0.001), low Ki67 (P<0.001), low/intermediate Oncotype DX recurrence scores (P<0.001), and prolonged event-free survival (P=0.003). BCs from GEM models were all AP-2β-negative. In human BC cell lines, AP-2β expression was independent from ER-signaling. SiRNA-mediated inhibition of AP-2β diminished proliferation of lobular BC cell lines in vitro. In summary, AP-2β is a new mammary epithelial differentiation marker. Its expression is preferentially retained and enhanced in LCIS and invasive lobular BC and has prognostic implications. Our findings indicate that AP-2β controls tumor cell proliferation in this slow-growing BC subtype.

Neelamraju Y, Gonzalez-Perez A, Bhat-Nakshatri P, et al.
Mutational landscape of RNA-binding proteins in human cancers.
RNA Biol. 2018; 15(1):115-129 [PubMed] Free Access to Full Article Related Publications
RNA Binding Proteins (RBPs) are a class of post-transcriptional regulatory molecules which are increasingly documented to be dysfunctional in cancer genomes. However, our current understanding of these alterations is limited. Here, we delineate the mutational landscape of ∼1300 RBPs in ∼6000 cancer genomes. Our analysis revealed that RBPs have an average of ∼3 mutations per Mb across 26 cancer types. We identified 281 RBPs to be enriched for mutations (GEMs) in at least one cancer type. GEM RBPs were found to undergo frequent frameshift and inframe deletions as well as missense, nonsense and silent mutations when compared to those that are not enriched for mutations. Functional analysis of these RBPs revealed the enrichment of pathways associated with apoptosis, splicing and translation. Using the OncodriveFM framework, we also identified more than 200 candidate driver RBPs that were found to accumulate functionally impactful mutations in at least one cancer. Expression levels of 15% of these driver RBPs exhibited significant difference, when transcriptome groups with and without deleterious mutations were compared. Functional interaction network of the driver RBPs revealed the enrichment of spliceosomal machinery, suggesting a plausible mechanism for tumorogenesis while network analysis of the protein interactions between RBPs unambiguously revealed the higher degree, betweenness and closeness centrality for driver RBPs compared to non-drivers. Analysis to reveal cancer-specific Ribonucleoprotein (RNP) mutational hotspots showed extensive rewiring even among common drivers between cancer types. Knockdown experiments on pan-cancer drivers such as SF3B1 and PRPF8 in breast cancer cell lines, revealed cancer subtype specific functions like selective stem cell features, indicating a plausible means for RBPs to mediate cancer-specific phenotypes. Hence, this study would form a foundation to uncover the contribution of the mutational spectrum of RBPs in dysregulating the post-transcriptional regulatory networks in different cancer types.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. GMNN, Cancer Genetics Web: Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 31 August, 2019     Cancer Genetics Web, Established 1999