HNF4α: a new biomarker in colon cancer?
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ABSTRACT:
SUBMITTER: Chellappa K
PROVIDER: S-EPMC3581081 | biostudies-literature | 2012 Jun
REPOSITORIES: biostudies-literature
Publications
HNF4α: a new biomarker in colon cancer?
Chellappa Karthikeyani K Robertson Graham R GR Sladek Frances M FM
Biomarkers in medicine 20120601 3
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Project description:Src tyrosine kinase has long been implicated in colon cancer but much remains to be learned about its substrates. The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) has just recently been implicated in colon cancer but its role is poorly defined. Here we show that c-Src phosphorylates human HNF4α on three tyrosines in an interdependent and isoform-specific fashion. The initial phosphorylation site is a Tyr residue (Y14) present in the N-terminal A/B domain of P1- but not P2-driven HNF4α. Phospho-Y14 interacts with the Src SH2 domain, leading to the phosphorylation of two additional tyrosines in the ligand binding domain (LBD) in P1-HNF4α. Phosphomimetic mutants in the LBD decrease P1-HNF4α protein stability, nuclear localization and transactivation function. Immunohistochemical analysis of approximately 450 human colon cancer specimens (Stage III) reveals that P1-HNF4α is either lost or localized in the cytoplasm in approximately 80% of tumors, and that staining for active Src correlates with those events in a subset of samples. Finally, three SNPs in the human HNF4α protein, two of which are in the HNF4α F domain that interacts with the Src SH3 domain, increase phosphorylation by Src and decrease HNF4α protein stability and function, suggesting that individuals with those variants may be more susceptible to Src-mediated effects. This newly identified interaction between Src kinase and HNF4α has important implications for colon and other cancers.
| S-EPMC3289305 | biostudies-literature
Project description:BACKGROUND:The aim was to identify a novel prognostic miRNA signature for colon cancer (CC) in silico. METHODS:Data on the expression of miRNAs and relevant clinical information for 407 patients were obtained from The Cancer Genome Atlas (TCGA), and the samples were randomly split into a validation set (n = 203) and training set (n = 204). The differential expression of miRNAs between normal tissues and patients with CC was analyzed. We detected a miRNA expression signature in the training dataset by using a Cox proportional hazard regression model. Then, we verified the signature in the validation set. Association of the miRNA signature with overall survival was assessed in the validation cohort and combined cohort by log-rank test and based on Kaplan-Meier curves. The receiver operating characteristic and disease-free survival analyses were performed to evaluate the miRNA signature of CC in the combined cohort. Multivariate and univariate Cox analyses related to survival for the miRNA signature were performed, and a nomogram was built as a prognostic model for CC. To explore the function of target genes of the miRNA signature, Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were used. RESULTS:Between the matched normal tissues and colon cancer tissues, 267 differentially expressed miRNAs were detected, and a single-factor CoxPH model showed that 13 miRNAs were related to overall survival in the training cohort. Then, a five-miRNA signature was identified using a CoxPH regression model with multiple factors. The five-miRNA signature had significant prognostic value in the training cohort and was validated in the validation cohort and combined cohort. A total of 193 target genes of the miRNA signature were identified. According to the results of functional analysis of the target genes, the signaling pathways MAPK, AMPK and PI3K-Akt, focal adhesion, and microRNAs in cancer were remarkably enriched. CONCLUSION:A five-miRNA signature had increased prognostic value for CC, which may provide important biological insights for the discovery and development of molecular predictors to improve the prognosis of patients with CC.
| S-EPMC7015317 | biostudies-literature
Project description:HNF4α has been implicated in colitis and colon cancer in humans but the role of the different HNF4α isoforms expressed from the two different promoters (P1 and P2) active in the colon is not clear. Here, we show that P1-HNF4α is expressed primarily in the differentiated compartment of the mouse colonic crypt and P2-HNF4α in the proliferative compartment. Exon swap mice that express only P1- or only P2-HNF4α have different colonic gene expression profiles, interacting proteins, cellular migration, ion transport and epithelial barrier function. The mice also exhibit altered susceptibilities to experimental colitis (DSS) and colitis-associated colon cancer (AOM+DSS). When P2-HNF4α-only mice (which have elevated levels of the cytokine resistin-like β, RELMβ, and are extremely sensitive to DSS) are crossed with Retnlb(-/-) mice, they are rescued from mortality. Furthermore, P2-HNF4α binds and preferentially activates the RELMβ promoter. In summary, HNF4α isoforms perform non-redundant functions in the colon under conditions of stress, underscoring the importance of tracking them both in colitis and colon cancer.
| S-EPMC4907689 | biostudies-literature
Project description:Chemokines are important in the development and progression of tumors. We investigated the expression of CXCL14 and CXCL16 in colon cancer. Expression of mRNA was assessed in primary tumors and lymph nodes and CXCL16 mRNA levels were correlated to patient's survival. Protein expression was investigated by two-color immunofluorescence and immunomorphometry. CXCL14 and CXCL16 mRNA levels and protein expression were significantly higher in colon cancer primary tumors compared to apparently normal colon tissue. Positive cells were tumor cells, as revealed by anti-CEA and anti-EpCAM staining. CXCL16, but not CXCL14, mRNA levels were significantly higher in hematoxylin and eosin positive (H&E(+)) compared to H&E(-) colon cancer lymph nodes or control nodes (P < 0.0001). CXCL16 mRNA was expressed in 5/5 colon cancer cell lines while CXCL14 was expressed significantly in only one. Kaplan-Meier analysis revealed that colon cancer patients with lymph nodes expressing high or very high levels (7.2 and 11.4 copies/18S rRNA unit, respectively) of CXCL16 mRNA had a decreased mean survival time of 30 and 46 months at the 12-year follow-up (P = 0.04, P = 0.005, respectively). In conclusion, high expression of CXCL16 mRNA in regional lymph nodes of colon cancer patients is a sign of a poor prognosis.
| S-EPMC6888697 | biostudies-literature
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| S-EPMC7521111 | biostudies-literature
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| S-EPMC4955394 | biostudies-literature
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| S-EPMC478209 | biostudies-literature
Project description:Hepatocyte nuclear factor 4alpha (HNF4α) is a nuclear receptor with an emerging role in the gut. While HNF4α has been implicated in colitis and colon cancer in humans, deciphering its functional role is complicated by the existence of two promoters (P1 and P2) in theHNF4A gene that drive the expression of multiple isoforms in the adult intestine. In this study we investigate the roles of P1- and P2-driven HNF4α under conditions of homeostasis, colitis and colitis-associated colon cancer (CAC). P1- and P2-HNF4α are differentially expressed in the differentiated and proliferative compartments of the normal colonic crypt, respectively. Expression profiling of untreated exon swap mice suggests distinct functions of the isoforms that were corroborated in migration and ion transport assays.
2016-05-23 | GSE47731 | GEO
Project description:ObjectiveTo evaluate the expression of retinoid-related orphan receptor gamma (RORγ) and its potential role in the prognosis of colon cancer.MethodsThe Cancer Genome Atlas and GSE117606 were used to evaluate to RORγ levels in colon cancer, and real-time quantitative polymerase chain reaction was applied for validation. UALCAN and MEXPRESS were used to analyze the associations of RORγ expression with clinical parameters. The survival analysis was conducted in GEPIA.ResultsRORγ expression was significantly lower in colon tumors than in adjacent normal mucosa tissues. RORγ expression was significantly associated with tumor stage, lymph node metastasis, and liver metastasis. The area under the curve for diagnosis was 0.71. Decreased RORγ expression was positively correlated with the incidence of lymphatic invasion, microsatellite instability, the presence of residual tumor, venous invasion, and copy number variation. Overall survival was longer in patients with higher RORγ expression, especially those with microsatellite instability-high features. Methylation analysis revealed that hypermethylation of the RORγ promoter was associated with the colon cancer stage.ConclusionsRORγ downregulation could be a potential biomarker for colon cancer, especially for predicting prognosis. Decreased RORγ expression in colon tumor may be associated with promoter hypermethylation.
| S-EPMC8113924 | biostudies-literature
Project description:BackgroundColorectal cancer (CRC) is the third most commonly diagnosed cancer in men and women globally. Investigating genetic ground differences between normal and CRC tissues would be significant for identifying some key oncogenic pathways and developing anti-cancer agents.MethodsWeighted gene co-expression network analysis (WGCNA) method was used to screen out core pathways related to the clinical traits of CRC patients. Then, multiple databases were utilized to further verify the hub genes obtained from data mining. Finally, to explore the role of hub genes in CRC, cell counting and EdU assays were performed.ResultsThe results of the WGCNA analysis showed that a module (turquoise module) was highly related with CRC differentiation grade (R =0.53, P<0.0001). Enrichment analysis indicated that genes of the turquoise module were remarkably enriched in multiple inflammatory processes and pathways. Among all hub genes of the turquoise module, the mRNA levels of STAT1 and CCL5 were significantly higher in CRC than in normal colon tissues. STAT1 expression was highly positively correlated with the level of CCL5. The results of the cell counting, EdU, CCK-8, and CFSE staining assays showed that interfering with STAT1 and CCL5 could inhibit the proliferation of CRC cells.ConclusionsOur study indicated that the STAT1-CCL5 axis is an important modulator in the development of CRC through promoting cell proliferation. Moreover, the levels of STAT1 and CCL5 might be valuable biomarkers for CRC screening.
| S-EPMC7475405 | biostudies-literature