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 (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).
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
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: HNF1A (cancer-related)
Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (PHH) they are widely used for pre-screening tests of drug metabolism and toxicity. The aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizing activities towards PHH. It is well-known that epigenetics is strongly modified in tumor cells and that epigenetic regulators influence the expression and function of Cytochrome P450 (CYP) enzymes through altering crucial transcription factors responsible for drug-metabolizing enzymes. Therefore, we screened the epigenetic status of four different liver cancer cell lines (Huh7, HLE, HepG2 and AKN-1) which were reported to have metabolizing drug activities. Our results showed that HepG2 cells demonstrated the highest similarity compared to PHH. Thus, we modified the epigenetic status of HepG2 cells towards 'normal' liver cells by 5-Azacytidine (5-AZA) and Vitamin C exposure. Then, mRNA expression of Epithelial-mesenchymal transition (EMT) marker SNAIL and CYP enzymes were measured by PCR and determinate specific drug metabolites, associated with CYP enzymes by LC/MS. Our results demonstrated an epigenetic shift in HepG2 cells towards PHH after exposure to 5-AZA and Vitamin C which resulted in a higher expression and activity of specific drug metabolizing CYP enzymes. Finally, we observed that 5-AZA and Vitamin C led to an increased expression of Hepatocyte nuclear factor 4α (HNF4α) and E-Cadherin and a significant down regulation of Snail1 (SNAIL), the key transcriptional repressor of E-Cadherin. Our study shows, that certain phase I genes and their enzyme activities are increased by epigenetic modification in HepG2 cells with a concomitant reduction of EMT marker gene SNAIL. The enhancing of liver specific functions in hepatoma cells using epigenetic modifiers opens new opportunities for the usage of cell lines as a potential liver in vitro model for drug testing and development.
The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. We genotyped 64 PanNETs and found 58% carry ATRX, DAXX, and MEN1 mutations (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis to reveal two distinct subgroups with one consisting entirely of A-D-M mutant PanNETs. Two genes differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha-cells (FDR q-value < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.
Liu X, Luo X, Wu Y, et al.MicroRNA-34a Attenuates Paclitaxel Resistance in Prostate Cancer Cells via Direct Suppression of JAG1/Notch1 Axis.
Cell Physiol Biochem. 2018; 50(1):261-276 [PubMed
] Related Publications
BACKGROUND/AIMS: Treatment options for metastatic castrate-resistant prostate cancer (mCRPC) are limited and typically centered on paclitaxel-based chemotherapy. In this study, we aimed to evaluate whether miR-34a attenuates chemoresistance to paclitaxel by regulating target genes associated with drug resistance.
METHODS: We used data from The Cancer Genome Atlas to compare miR-34a expression levels in prostate cancer (PC) tissues with normal prostate tissues. The effects of miR-34a inhibition and overexpression on PC proliferation were evaluated in vitro via Cell Counting Kit-8 (CCK-8) proliferation, colony formation, apoptosis, and cell-cycle assays. A luciferase reporter assay was employed to identify the interactions between miR-34a and specific target genes. To determine the effects of up-regulation of miR-34a on tumor growth and chemo-resistance in vivo, we injected PC cells overexpressing miR-34a into nude mice subcutaneously and evaluated the rate of tumor growth during paclitaxel treatment. We examined changes in the expression levels of miR-34a target genes JAG1 and Notch1 and their downstream genes via miR-34a transfection by quantitative reverse transcription PCR (qRT-PCR) and western blot assay.
RESULTS: miR-34a served as an independent predictor of reduced patient survival. MiR-34a was down-regulated in PC-3PR cells compared with PC-3 cells. The CCK-8 assay showed that miR-34a overexpression resulted in increased sensitivity to paclitaxel while miR-34a down-regulation resulted in chemoresistance to paclitaxel in vitro. A study of gain and loss in a series of functional assays revealed that PC cells expressing miR-34a were chemosensitive. Furthermore, the overexpression of miR-34a increased the sensitivity of PC-3PR cells to chemotherapy in vivo. The luciferase reporter assay confirmed that JAG1 and Notch1 were directly targeted by miR-34a. Interestingly, western blot analysis and qRT-PCR confirmed that miR-34a inhibited the Notch1 signaling pathway. We found that miR-34a increased the chemosensitivity of PC-3PR cells by directly repressing the TCF1/ LEF1 axis.
CONCLUSION: Our results showed that miR-34a is involved in the development of chemosensitivity to paclitaxel. By regulating the JAG1/Notch1 axis, miR-34a or its target genes JAG1 or Notch1 might serve as potential predictive biomarkers of response to paclitaxel-based chemotherapy and/or therapeutic targets that will help to overcome chemoresistance at the mCRPC stage.
Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.
Yan H, Wang Q, Shen Q, et al.Identification of potential transcription factors, long noncoding RNAs, and microRNAs associated with hepatocellular carcinoma.
J Cancer Res Ther. 2018; 14(Supplement):S622-S627 [PubMed
] Related Publications
Aim: This study aimed to investigate the key transcription factors (TFs), long noncoding RNAs (lncRNAs), and microRNAs (miRNAs) associated with hepatocellular carcinoma (HCC).
Materials and Methods: The datasets GSE31383 and GSE54238 were downloaded from Gene Expression Omnibus data repository. GSE31383 was used to screen differentially expressed miRNAs, and GSE54238 was used to screen differentially expressed messenger RNAs (mRNAs) and lncRNAs. ChipBase was used to identify TF-miRNA pairs. StarBase was selected to identify miRNA-mRNA and lncRNA-miRNA interactions. Kyoto Encyclopedia of Genes and Genomes pathway analysis was also conducted using Database for Annotation, Visualization, and Integrated Discovery tool.
Results: A total of 2065 mRNAs, 1050 lncRNAs, and 26 miRNAs were identified to be divergently expressed in HCC compared with normal tissues. There were 338 miRNA-mRNA and 65 lncRNA-miRNA pairs with reverse expression trend. Besides 249 TF-miRNA relationships including differentially expressed miRNA were isolated. Among them, 11 TF-miRNA had the same expression trend. Furthermore, lncRNA-miRNA-mRNA and TF-miRNA-mRNA regulatory networks were constructed. hsa-miR-497, hsa-miR-195, and hsa-miR-424 were identified as hub nodes in these two networks. Hub TFs, such as TATA box binding protein-associated factor 1 (TAF1) and hepatocyte nuclear factor 4, alpha (HNF4α), and lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were also screened out in the network.
Conclusions: Our findings highlight the regulatory networks among TFs, lncRNAs, miRNAs, and mRNAs in HCC. Several key molecules, such as hsa-miR-195, lncRNA MALAT1 and TFs TAF1 and HNF4α, may contribute to the progression of HCC.
Hepatocyte nuclear factor 4α (HNF4α) is a critical factor for hepatocyte differentiation. HNF4α expression is decreased in hepatocellular carcinoma (HCC), which suggests a role in repression of hepatocyte dedifferentiation. In the present study, hepatic expression of HNF4γ was increased in liver-specific
Hepatocellular carcinoma (HCC) accounts for a large proportion of liver cancer cases and has an extremely poor prognosis. Therefore, novel innovative therapies for HCC are strongly desired. As gene therapy tools for HCC, 2 hepatic transcription factors (TF), HNF4A and HNF1A, have been used to suppress proliferation and to extinguish cancer-specific characteristics of target cells. However, our present data demonstrated that single transduction of HNF4A or HNF1A had only a limited effect on suppression of HCC cell proliferation. Thus, in this study, we examined whether combinations of TF could show more effective antitumor activity, and found that combinatorial transduction of 3 hepatic TF, HNF4A, HNF1A and FOXA3, suppressed HCC cell proliferation more stably than single transduction of these TF. The combinatorial transduction also suppressed cancer-specific phenotypes, such as anchorage-independent growth in culture and tumorigenicity after transplantation into mice. HCC cell lines transduced with the 3 TF did not recover their proliferative property after withdrawal of anticancer drugs, indicating that combinatorial expression of the 3 TF suppressed the growth of all cell subtypes within the HCC cell lines, including cancer stem-like cells. Transcriptome analyses revealed that the expression levels of a specific gene set involved in cell proliferation were only decreased in HCC cells overexpressing all 3 TF. Moreover, combined transduction of the 3 TF could facilitate hepatic differentiation of HCC cell lines. Our strategy for inducing stable inhibition and functional differentiation of tumor cells using a defined set of TF will become an effective therapeutic strategy for various types of cancers.
Stumm J, Vallecillo-García P, Vom Hofe-Schneider S, et al.Odd skipped-related 1 (Osr1) identifies muscle-interstitial fibro-adipogenic progenitors (FAPs) activated by acute injury.
Stem Cell Res. 2018; 32:8-16 [PubMed
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Fibro-adipogenic progenitors (FAPs) are resident mesenchymal progenitors in adult skeletal muscle that support muscle repair, but also give rise to fibrous and adipose infiltration in response to disease and chronic injury. FAPs are identified using cell surface markers that do not distinguish between quiescent FAPs and FAPs actively engaged in the regenerative process. We have shown previously that FAPs are derived from cells that express the transcription factor Osr1 during development. Here we show that adult FAPs express Osr1 at low levels and frequency, however upon acute injury FAPs reactivate Osr1 expression in the injured tissue. Osr1
Kim HD, Song GW, Park S, et al.Association Between Expression Level of PD1 by Tumor-Infiltrating CD8
Gastroenterology. 2018; 155(6):1936-1950.e17 [PubMed
] Related Publications
BACKGROUND & AIMS: T-cell exhaustion, or an impaired capacity to secrete cytokines and proliferate with overexpression of immune checkpoint receptors, occurs during chronic viral infections but has also been observed in tumors, including hepatocellular carcinomas (HCCs). We investigated features of exhaustion in CD8
METHODS: We obtained HCC specimens, along with adjacent nontumor tissues and blood samples, from 90 patients who underwent surgical resection at Asan Medical Center (Seoul, Korea) from April 2016 through April 2018. Intrahepatic lymphocytes and tumor-infiltrating T cells were analyzed by flow cytometry. Tumor-infiltrating CD8
RESULTS: PD1-high, PD1-intermediate, and PD1-negative CD8
CONCLUSIONS: We found HCC specimens to contain CD8
The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of
Donner I, Katainen R, Sipilä LJ, et al.Germline mutations in young non-smoking women with lung adenocarcinoma.
Lung Cancer. 2018; 122:76-82 [PubMed
] Related Publications
OBJECTIVES: Although the primary cause of lung cancer is smoking, a considerable proportion of all lung cancers occur in never smokers. Gender influences the risk and characteristics of lung cancer and women are overrepresented among never smokers with the disease. Young age at onset and lack of established environmental risk factors suggest genetic predisposition. In this study, we used population-based sampling of young patients to discover candidate predisposition variants for lung adenocarcinoma in never-smoking women.
MATERIALS AND METHODS: We employed archival normal tissue material from 21 never-smoker women who had been diagnosed with lung adenocarcinoma before the age of 45, and exome sequenced their germline DNA.
RESULTS AND CONCLUSION: Potentially pathogenic variants were found in eight Cancer Gene Census germline genes: BRCA1, BRCA2, ERCC4, EXT1, HNF1 A, PTCH1, SMARCB1 and TP53. The variants in TP53, BRCA1, and BRCA2 are likely to have contributed to the early onset lung cancer in the respective patients (3/21 or 14%). This supports the notion that lung adenocarcinoma can be a component of certain cancer predisposition syndromes. Fifteen genes displayed potentially pathogenic mutations in at least two patients: ABCC10, ATP7B, CACNA1S, CFTR, CLIP4, COL6A1, COL6A6, GCN1, GJB6, RYR1, SCN7A, SEC24A, SP100, TTN and USH2A. Four patients showed a mutation in COL6A1, three in CLIP4 and two in the rest of the genes. Some of these candidate genes may explain a subset of female lung adenocarcinoma.
Liu X, Liu X, Wu Y, et al.MicroRNA-34a Attenuates Metastasis and Chemoresistance of Bladder Cancer Cells by Targeting the TCF1/LEF1 Axis.
Cell Physiol Biochem. 2018; 48(1):87-98 [PubMed
] Related Publications
BACKGROUND/AIMS: Chemoresistance is largely responsible for relapses of bladder cancer during clinical therapy. However, the molecular mechanisms involved in the chemoresistance of bladder cancer are unclear. Growing evidence supports the theory that microRNAs (miRNAs) play an important role in chemotherapeutic drug resistance because they are downregulated in many malignancies that have been implicated in the regulation of diverse processes in cancer cells. More specifically, the extent and precise mechanism of the involvement of miR-34as in chemoresistance to epirubicin (EPI) in the treatment of bladder cancer remains unclear.
METHODS: In this study, real-time quantitative polymerase chain reaction (PCR) was used to analyze the expression of miR-34a in bladder cancer cell line BIU87 and its EPI chemoresistant cell line BIU87/ADR. The miR-34a profiles in bladder cancer tissues were obtained from The Cancer Genome Atlas database. The effect of miR-34a on chemosensitivity was evaluated by cell viability assays, colony formation assays, and in vivo experimentation. Apoptosis and the cell cycle were examined by flow cytometry. A luciferase reporter assay was used to assess the target genes of miR-34a. Western blot and qPCR were used to analyze the expression of target proteins and downstream molecules.
RESULTS: The downregulation of miR-34a in bladder cancer serves as an independent predictor of reduced patient survival. The CCK-8 assay showed that miR-34a overexpression resulted in increased sensitivity to EPI, while miR-34a downregulation resulted in chemoresistance to EPI in vitro. Moreover, it was found that miR-34a increased the sensitivity of BIU87/ADR cells to chemotherapy in vivo. The luciferase reporter assay ascertained that TCF1 and LEF1 are direct target genes of miR-34a. It was found that miR-34a increased chemosensitivity in BIU87/ADR cells by inhibiting the TCF1/LEF1 axis.
CONCLUSIONS: The results of this study indicate that miR-34a contributes to the chemosensitivity of BIU87/ADR by inhibiting the TCF1/LEF1 axis. Consequently, miR-34a is a determinant of BIU87 chemosensitivity and may therefore serve as a potential therapeutic target in bladder cancer treatment.
Yang YC, Fu WP, Zhang J, et al.rs401681 and rs402710 confer lung cancer susceptibility by regulating TERT expression instead of CLPTM1L in East Asian populations.
Carcinogenesis. 2018; 39(10):1216-1221 [PubMed
] Related Publications
Lung cancer is a common cancer in human and has presented significant genetic predisposition. Previous genome-wide association study observed that rs401681 within CLPTM1L (CLPTM1 like) was significantly associated with lung cancer. By analyzing 1000 genomes data for East Asian, we identified only one SNP in nearby region, rs402710, in high linkage disequilibrium with rs401681, which was also associated with lung cancer. However, the real causal SNP and mechanism for the association were still not clear. The following plasmid construction, mutagenesis, transient transfection and luciferase reading indicated that both SNPs could regulate gene expression in lung/bronchial epithelium Beas-2B cell line. By chromosome conformation capture, it was identified that the segment containing these two SNPs could interact with TERT (telomerase reverse transcriptase) promoter, thus indicating that these SNPs confer lung cancer risk by regulating TERT expression instead of CLPTM1L. Through chromatin immunoprecipitation, the transcript factors HNF4A (hepatocyte nuclear factor 4 alpha) and MAF1 (MAF1 homolog, negative regulator of RNA polymerase III) were recognized for the regions spanning rs401681 and rs402710, respectively. Our results uncovered a complete link between these two SNPs and lung cancer.
Cheng JC, Wang EY, Yi Y, et al.S1P Stimulates Proliferation by Upregulating CTGF Expression through S1PR2-Mediated YAP Activation.
Mol Cancer Res. 2018; 16(10):1543-1555 [PubMed
] Related Publications
Dysregulation of the Hippo pathway in the liver results in overgrowth and eventually tumorigenesis. To date, several upstream mechanisms have been identified that affect the Hippo pathway, which ultimately regulate YAP, the major downstream effector of the pathway. However, upstream regulators of the Hippo pathway in the liver remain poorly defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that has been shown to stimulate hepatocellular carcinoma (HCC) cell proliferation, but whether the Hippo pathway is involved in S1P-stimulated HCC cell proliferation remains to be determined. Here it is demonstrated that S1P activates YAP and that the S1P receptor 2 (S1PR2/S1P2) mediates S1P-induced YAP activation in both human and mouse HCC cells. S1P promotes YAP-mediated upregulation of cysteine-rich protein 61 and connective tissue growth factor (CTGF), and stimulates HCC cell proliferation. By using siRNA-mediated knockdown approaches, only CTGF was required for S1P-stimulated cell proliferation. Of note, S1P activates YAP in a MST1/2-independent manner suggesting that the canonical Hippo kinase is not required for S1P-mediated proliferation in liver. The upregulation of CTGF and S1P2 were also observed in liver-specific YAP overexpression transgenic mouse hepatocytes. Moreover, YAP regulated liver differentiation-dependent gene expression by influencing the chromatin binding of HNF4α based on ChIP-seq analysis. Finally, results using gain- and loss-of-function approaches demonstrate that HNF4α negatively regulated S1P-induced CTGF expression.
Hepatitis C virus (HCV) infection is closely associated with type 2 diabetes. We reported that HCV infection induces the lysosomal degradation of hepatocyte nuclear factor 1 alpha (HNF-1α) via interaction with HCV nonstructural protein 5A (NS5A) protein, thereby suppressing GLUT2 gene expression. The molecular mechanisms of selective degradation of HNF-1α caused by NS5A are largely unknown. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway. Here, we investigated whether CMA is involved in the selective degradation of HNF-1α in HCV-infected cells and observed that the pentapeptide spanning from amino acid (aa) 130 to aa 134 of HNF-1α matches the rule for the CMA-targeting motif, also known as KFERQ motif. A cytosolic chaperone protein, heat shock cognate protein of 70 kDa (HSC70), and a lysosomal membrane protein, lysosome-associated membrane protein type 2A (LAMP-2A), are key components of CMA. Immunoprecipitation analysis revealed that HNF-1α was coimmunoprecipitated with HSC70, whereas the Q130A mutation (mutation of Q to A at position 130) of HNF-1α disrupted the interaction with HSC70, indicating that the CMA-targeting motif of HNF-1α is important for the association with HSC70. Immunoprecipitation analysis revealed that increasing amounts of NS5A enhanced the association of HNF-1α with HSC70. To determine whether LAMP-2A plays a role in the degradation of HNF-1α protein, we knocked down LAMP-2A mRNA by RNA interference; this knockdown by small interfering RNA (siRNA) recovered the level of HNF-1α protein in HCV J6/JFH1-infected cells. This result suggests that LAMP-2A is required for the degradation of HNF-1α. Immunofluorescence study revealed colocalization of NS5A and HNF-1α in the lysosome. Based on our findings, we propose that HCV NS5A interacts with HSC70 and recruits HSC70 to HNF-1α, thereby promoting the lysosomal degradation of HNF-1α via CMA.
Lung cancer is the leading cause of cancer-related deaths worldwide, with lung adenocarcinoma representing the most common lung cancer subtype. Among all lung adenocarcinomas, the most prevalent subset develops via tumorigenesis and progression from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to minimally invasive adenocarcinoma (MIA), to overt invasive adenocarcinoma with a lepidic pattern. This stepwise development is supported by the clinicopathological and molecular characteristics of these tumors. In the 2015 World Health Organization classification, AAH and AIS are both defined as preinvasive lesions, whereas MIA is identified as an early invasive adenocarcinoma that is not expected to recur if removed completely. Recent studies have examined the molecular features of lung adenocarcinoma tumorigenesis and progression.
Seshachalam VP, Sekar K, Hui KMInsights into the etiology-associated gene regulatory networks in hepatocellular carcinoma from The Cancer Genome Atlas.
J Gastroenterol Hepatol. 2018; 33(12):2037-2047 [PubMed
] Related Publications
BACKGROUND AND AIM: Hepatitis B virus (HBV), hepatitis C virus, alcohol consumption, and non-alcoholic fatty liver disease are the major known risk factors for hepatocellular carcinoma (HCC). There have been very few studies comparing the underlying biological mechanisms associated with the different etiologies of HCC. In this study, we hypothesized the existence of different regulatory networks associated with different liver disease etiologies involved in hepatocarcinogenesis.
METHODS: Using upstream regulatory analysis tool in ingenuity pathway analysis software, upstream regulators (URs) were predicted using differential expressed genes for HCC to facilitate the interrogation of global gene regulation.
RESULTS: Analysis of regulatory networks for HBV HCC revealed E2F1 as activated UR, regulating genes involved in cell cycle and DNA replication, and HNF4A and HNF1A as inhibited UR. In hepatitis C virus HCC, interferon-γ, involved in cellular movement and signaling, was activated, while IL1RN, mitogen-activated protein kinase 1 involved in interleukin 22 signaling and immune response, was inhibited. In alcohol consumption HCC, ERBB2 involved in inflammatory response and cellular movement was activated, whereas HNF4A and NUPR1 were inhibited. For HCC derived from non-alcoholic fatty liver disease, miR-1249-5p was activated, and NUPR1 involved in cell cycle and apoptosis was inhibited. The prognostic value of representative genes identified in the regulatory networks for HBV HCC can be further validated by an independent HBV HCC dataset established in our laboratory with survival data.
CONCLUSIONS: Our study identified functionally distinct candidate URs for HCC developed from different etiologic risk factors. Further functional validation studies of these regulatory networks could facilitate the management of HCC towards personalized medicine.
Wattanavanitchakorn S, Rojvirat P, Chavalit T, et al.CCAAT-enhancer binding protein-α (C/EBPα) and hepatocyte nuclear factor 4α (HNF4α) regulate expression of the human fructose-1,6-bisphosphatase 1 (FBP1) gene in human hepatocellular carcinoma HepG2 cells.
PLoS One. 2018; 13(3):e0194252 [PubMed
] Free Access to Full Article Related Publications
Fructose-1,6-bisphosphatase (FBP1) plays an essential role in gluconeogenesis. Here we report that the human FBP1 gene is regulated by two liver-enriched transcription factors, CCAAT-enhancer binding protein-α (C/EBPα) and hepatocyte nuclear factor 4α (HNF4α) in human hepatoma HepG2 cells. C/EBPα regulates transcription of FBP1 gene via binding to the two overlapping C/EBPα sites located at nucleotide -228/-208 while HNF4α regulates FBP1 gene through binding to the classical H4-SBM site and direct repeat 3 (DR3) located at nucleotides -566/-554 and -212/-198, respectively. Mutations of these transcription factor binding sites result in marked decrease of C/EBPα- or HNF4α-mediated transcription activation of FBP1 promoter-luciferase reporter expression. Electrophoretic mobility shift assays of -228/-208 C/EBPα or -566/-554 and -212/-198 HNF4α sites with nuclear extract of HepG2 cells overexpressing C/EBPα or HNF4α confirms binding of these two transcription factors to these sites. Finally, we showed that siRNA-mediated suppression of C/EBPα or HNF4α expression in HepG2 cells lowers expression of FBP1 in parallel with down-regulation of expression of other gluconeogenic enzymes. Our results suggest that an overall gluconeogenic program is regulated by these two transcription factors, enabling transcription to occur in a liver-specific manner.
Nuclear activated β-catenin plays a causative role in colorectal cancers (CRC) but remains an elusive therapeutic target. Using human CRC cells harboring different Wnt/β-catenin pathway mutations in APC/KRAS or β-catenin/KRAS genes, and both genetic and pharmacological knockdown approaches, we show that oncogenic β-catenin signaling negatively regulates the expression of NHERF1 (Na
BACKGROUND: Our previous study has demonstrated that hepatocyte nuclear factor 1α (HNF1α) exerts potent therapeutic effects on hepatocellular carcinoma (HCC). However, the molecular mechanisms by which HNF1α reverses HCC malignancy need to be further elucidated.
METHODS: lncRNA microarray was performed to identify the long noncoding RNAs (lncRNAs) regulated by HNF1α. Chromatin immunoprecipitation and luciferase reporter assays were applied to clarify the mechanism of the transcriptional regulation of HNF1α to HNF1A antisense RNA 1 (HNF1A-AS1). The effect of HNF1A-AS1 on HCC malignancy was evaluated in vitro and in vivo. RNA pulldown, RNA-binding protein immunoprecipitation and the Bio-Layer Interferometry assay were used to validate the interaction of HNF1A-AS1 and Src homology region 2 domain-containing phosphatase 1 (SHP-1).
RESULTS: HNF1α regulated the expression of a subset of lncRNAs in HCC cells. Among these lncRNAs, the expression levels of HNF1A-AS1 were notably correlated with HNF1α levels in HCC cells and human HCC tissues. HNF1α activated the transcription of HNF1A-AS1 by directly binding to its promoter region. HNF1A-AS1 inhibited the growth and the metastasis of HCC cells in vitro and in vivo. Moreover, knockdown of HNF1A-AS1 reversed the suppressive effects of HNF1α on the migration and invasion of HCC cells. Importantly, HNF1A-AS1 directly bound to the C-terminal of SHP-1 with a high binding affinity (KD = 59.57 ± 14.29 nM) and increased the phosphatase activity of SHP-1. Inhibition of SHP-1 enzymatic activity substantially reversed the HNF1α- or HNF1A-AS1-induced reduction on the metastatic property of HCC cells.
CONCLUSIONS: Our data revealed that HNF1A-AS1 is a direct transactivation target of HNF1α in HCC cells and involved in the anti-HCC effect of HNF1α. HNF1A-AS1 functions as phosphatase activator through the direct interaction with SHP-1. These findings suggest that regulation of the HNF1α/HNF1A-AS1/SHP-1 axis may have beneficial effects in the treatment of HCC.
Mutant forms of p53 protein often possess protumorigenic functions, conferring increased survival and migration to tumor cells via their "gain-of-function" activity. Whether and how a common polymorphism in
OBJECTIVES: The objectives of this study were to assess if targeted investigation for tumor-specific mutations by ultradeep DNA sequencing of peritoneal washes of ovarian cancer patients after primary surgical debulking and chemotherapy, and clinically diagnosed as disease free, provides a more sensitive and specific method to assess actual treatment response and tailor future therapy and to compare this "molecular second look" with conventional cytology and histopathology-based findings.
METHODS/MATERIALS: We identified 10 patients with advanced-stage, high-grade serous ovarian cancer who had undergone second-look laparoscopy and for whom DNA could be isolated from biobanked paired blood, primary and recurrent tumor, and second-look peritoneal washes. A targeted 56 gene cancer-relevant panel was used for next-generation sequencing (average coverage, >6500×). Mutations were validated using either digital droplet polymerase chain reaction (ddPCR) or Sanger sequencing.
RESULTS: A total of 25 tumor-specific mutations were identified (median, 2/patient; range, 1-8). TP53 mutations were identified in at least 1 sample from all patients. All 5 pathology-based second-look positive patients were confirmed positive by molecular second look. Genetic analysis revealed that 3 of the 5 pathology-based negative second looks were actually positive. In the 2 patients, the second-look mutations were present in either the original primary or recurrent tumors. In the third, 2 high-frequency, novel frameshift mutations in MSH6 and HNF1A were identified.
CONCLUSIONS: The molecular second look detects tumor-specific evidence of residual disease and provides genetic insight into tumor evolution and future recurrences beyond standard pathology. In the precision medicine era, detecting and genetically characterizing residual disease after standard treatment will be invaluable for improving patient outcomes.
Zhang G, An X, Zhao H, et al.Long non-coding RNA HNF1A-AS1 promotes cell proliferation and invasion via regulating miR-17-5p in non-small cell lung cancer.
Biomed Pharmacother. 2018; 98:594-599 [PubMed
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Long non-coding RNA HNF1A-antisense 1 (lncRNA HNF1A-AS1) plays important roles in the progression of human tumors. The aim of this study is to unravel the underlying mechanism of HNF1A-AS1 in non-small cell lung cancer (NSCLC). In the present study, we found that HNF1A-AS1 was upregulation in NSCLC tissues and cell lines. High HNF1A-AS1 expression was associated with patients' advanced TNM stage and lymph node metastasis. Reduced HNF1A-AS1 expression inhibited lung cancer cells proliferation, invasion and increased cells apoptosis rate. Bioinformatics analysis and luciferase reporter assay revealed that HNF1A-AS1 interacted with miR-17-5p by directly targeting it. Rescue experiments showed that miR-17-5p suppression reversed the tumor-suppressing role of HNF1A-AS1 knockdown on NSCLC progression. Conclusion, our data indicated that lncRNA HNF1A-AS1 promoted lung cancer cells proliferation and invasion via regulating miR-17-5p, suggesting that HNF1A-AS1 could act as a potent therapeutic strategy for the treatment of NSCLC patients.
Naqvi AAT, Hasan GM, Hassan MIInvestigating the role of transcription factors of pancreas development in pancreatic cancer.
Pancreatology. 2018; 18(2):184-190 [PubMed
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Pancreatic cancer (PC) is the seventh most common cause of cancer-related deaths worldwide that kills more than 300,000 people every year. Prognosis of PC is very poor with a five-year survival rate about 5%. The most common and highly observed type of PC is pancreatic ductal adenocarcinoma (PDAC). It is preceded by the progression of precursor lesions such as Pancreatic Intraepithelial Neoplasia (PanIN), Intraductal Papillary Neoplasm (IPMN) and Mucinous Cystic Neoplasm (MCN). PanIN is the most common among these premalignant lesions. Genes orchestrating the origin and differentiation of cells during organogenesis have the tendency to produce tumor cells in response to activating or inactivating mutations. Based on the following premise, we discuss the role of transcription factors (TFs) of pancreas development and cell fate differentiation in PC. Pancreas/duodenum homeobox protein 1 (PDX1), Pancreas transcription factor 1 subunit alpha (PTF1A), Nuclear receptor subfamily 5 group A member 2 (NR5A2), Hepatocyte nuclear factor 1-alpha (HNF1A) and Hepatocyte nuclear factor 1-beta (HNF1B) play vital role in the development and differentiation of pancreatic precursor cells. Mutated KRAS induces abnormalities in the regular function of these TFs which in turn cause abnormal cell growth and proliferation that leads to cancer. Thus, these TFs are highly susceptible for the origin of PC. Therefore, we propose that these TFs can be treated as therapeutic targets for the development of anticancer drugs.
Su Y, Chen Z, Yan L, et al.Optimizing combination of liver-enriched transcription factors and nuclear receptors simultaneously favors ammonia and drug metabolism in liver cells.
Exp Cell Res. 2018; 362(2):504-514 [PubMed
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The HepG2 cell line is widely used in studying liver diseases because of its immortalization, but its clinical application is limited by its low expression of the urea synthesis key enzymes and cytochromes P450 (CYPs). On the basis of our previous work, we investigated the transcriptional regulation of arginase 1 (Arg1) and ornithine transcarbamylase (OTC) in HepG2 cells. We also screened for the optimal combination of liver enrichment transcription factors (LETFs) and xenobiotic nuclear receptors that can promote the expression of key urea synthases and five major CYPs in HepG2 cells. Thus, recombinant HepG2 cells were established. Results showed that C/EBPβ, not C/EBPα, could upregulate expression of Arg1 and PGC1α and HNF4α cooperatively regulate the expression of OTC. The two optimal combinations C/EBPβ+HNF4α+HNF6+PXR and C/EBPβ+HNF4α+HNF6+CAR were selected. Compared with the control cells, the recombinant HepG2 cells modified by the two optimal combinations exhibited enhanced ammonia metabolism and CYP enzyme activity. Moreover, the HepG2/(C/EBPβ+HNF4α+HNF6+PXR) cells more strongly reduced ammonia than any other combination tested in this study. The present work indicated that optimizing the combination of transcription factors will simultaneously promote hepatocyte ammonia metabolism and drug metabolism. The recombinant HepG2 liver cell line constructed by the optimal combination provided an improved alternative means for bioartificial liver applications and drug toxicity testing.
Xu X, Qin L, Tian Y, et al.Family-based analysis of GGT1 and HNF1A gene polymorphisms in patients with polycystic ovary syndrome.
Reprod Biomed Online. 2018; 36(1):115-119 [PubMed
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Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disease. Previous studies indicate that genes GGT1 and HNF1A may contribute to the abnormal glucose metabolism and altered lipid profile that are important clinical features of PCOS. In the current study, the correlation between polymorphisms in the GGT1 and HNF1A genes and PCOS was explored. A total of 310 family trios were studied and the transmission disequilibrium test (TDT) was used to assess the linkage between PCOS and three single-nucleotide polymorphisms (SNP) (rs4820599 of GGT1, rs7305618 and rs2393791 of HNF1A). No deviations from HWE were detected. None of the three SNP markers showed significant transmission disequilibrium in PCOS family trios (rs4820599: GGT1 gene, χ
Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance.
Zhang X, Xiong Y, Tang F, et al.Long noncoding RNA HNF1A-AS1 indicates a poor prognosis of colorectal cancer and promotes carcinogenesis via activation of the Wnt/β-catenin signaling pathway.
Biomed Pharmacother. 2017; 96:877-883 [PubMed
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Long non-coding RNAs (lncRNAs) have been identified to play critical roles in tumorigenesis. LncRNA HNF1A-AS1 has been suggested to act as an oncogene and serves as a novel prognostic biomarker for various cancer. However, the biological role and clinical significance of lncRNA HNF1A-AS1 in colorectal cancer (CRC) have yet to be fully elusive. Therefore, the present study was designed to determine the expression of lncRNA HNF1A-AS1 in patients with CRC, the role of lncRNA HNF1A-AS1 in CRC cells, as well as the underlying regulatory mechanisms. Our results indicated that the expression of lncRNA HNF1A-AS1 was significantly upregulated in both CRC tumor tissues and CRC cell lines in comparison with adjacent non-tumor tissues and the human normal colonic epithelial cell line (HcoEpiC). The Kaplan-Meier survival analysis further suggested that high expression of lncRNA HNF1A-AS1 might be an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in patients with CRC. Moreover, the area under the receiver operating characteristic (ROC) curve for HNF1A-AS1 was up to 0.8714, implying that HNF1A-AS1 had diagnostic significance as it could discriminate tumor tissues from nontumorous tissues. In addition, silencing of lncRNA HNF1A-AS1 abrogated the proliferation of CRC cells by MTS assay and clonogenic assay, arrested cell cycle at G0/G1 stage and reduced the migration and invasion in CRC cells. Finally, we found that decreased expression of lncRNA HNF1A-AS1 suppressed the Wnt/β-catenin signaling pathway activity by downregulating the expression of β-catenin,cyclinD1, and c-myc. In conclusion, these findings provide evidence that lncRNA HNF1A-AS1 may be considered as a new prognostic biomarker and therapeutic target in patients with CRC.
Ding CH, Deng LF, Chen F, et al.p.Q511L mutation of HNF1α in hepatocellular carcinoma suppresses the transcriptional activity and the anti-tumor effect of HNF1α.
Biochem Biophys Res Commun. 2018; 495(1):86-91 [PubMed
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Hepatocyte nuclear factor 1α (HNF1α) is a liver-enriched transcription factor that regulates many aspects of hepatocyte functions. Our previous studies have demonstrated that HNF1α has potent therapeutic effects on hepatocellular carcinoma (HCC). Mutations in HNF1α gene are frequently associated with maturity-onset diabetes of the young type 3 (MODY3) and hepatocellular adenomas. However, the association of HNF1α mutation and HCC remains elusive. In this study, the point mutation of HNF1α gene with c.A1532 > T/p.Q511L was identified in an HCC patient by exon-capture high-throughput sequencing. Mutation of c.A1532 > T/p.Q511L in HNF1α gene was only detected in the tumor tissue but not in the adjacent non-tumorous liver tissue of the patient. Luciferase reporter assay and real-time PCR revealed that mutation of p.Q511L reduced the transcriptional activity of HNF1α. Immunofluorescence staining and subcellular fraction analysis revealed that mutation of p.Q511L disturbed the intracellular localization of HNF1α in HCC cells. Moreover, the inhibitory effect of HNF1α on the proliferation, migration and invasion in HCC cells was also partially abolished by the mutation of p.Q511L. Our data suggested that the missense mutation of HNF1α (p.Q511L) may associate with the progression of HCC.
Zhao J, Adams A, Roberts B, et al.Protein arginine methyl transferase 1- and Jumonji C domain-containing protein 6-dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice.
Hepatology. 2018; 67(3):1109-1126 [PubMed
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Alcohol is a well-established risk factor for hepatocellular carcinoma (HCC), but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily protein arginine methyl transferase 1 (PRMT1), and a demethylase Jumonji C domain-containing protein 6 (JMJD6). The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair-fed mice. Using hepatocyte-specific PRMT1 knockout mice, we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of hepatocyte nuclear factor 4 alpha (Hnf4α), an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the (Hnf4α) promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol-fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol-associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R = 0.8; P < 0.01) between arginine methylation levels and Hnf4α expression in these specimens, suggesting that the above mechanism is relevant in patients.
CONCLUSION: Taken together, these data suggest that PRMT1 inhibition, such as induced by alcohol, may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. (Hepatology 2018;67:1109-1126).