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Hepatocyte Nuclear Factor 3? Plays a Suppressive Role in Colorectal Cancer Progression.

ABSTRACT: Background and Objective: Hepatocyte nuclear factor 3? (HNF3?) is a key transcription factor in the development of the gastrointestinal tract. However, only few studies have examined its' expression, function and potential clinical significance in colorectal cancer tumorigenesis and progression. Methods: HNF3? expression in colorectal cancer tissue samples of 174 patients was assessed by immunohistochemistry. The results were analyzed with respect to patients' clinicopathological characteristics and survival. Following the in vitro cell transfection, MTT, wound healing, and Transwell assays were used to test cell proliferation, migration, and invasion, respectively. Western blot was used to examine IL6, JAK1, and STAT3 protein expression. The potential for tumor formation was evaluated using a mouse xenograft model. Results: HNF3? expression was lower in colon cancer tissue compared to normal tissue and correlated with UICC clinical stage (P = 0.001), depth of invasion (P = 0.004), regional lymph node metastasis (P = 0.007), distant metastasis (P = 0.048), and poor survival (P < 0.001) in patients with colorectal cancer. Furthermore, HNF3? overexpression impeded proliferation, migration and invasion of SW480 cells via JAK-STAT3 signaling in vitro. Moreso, HNF3? overexpression showed a significant growth inhibition of subcutaneous xenograft tumors in vivo. Conclusions: The results show that HNF3? acts as a suppressor of colorectal cancer progression and decreased HNF3 ? expression is closely related to the poor prognosis. Thus, HNF3? may be a potential molecular target for inhibition of colorectal cancer cells and development of new anti-tumor therapies.

SUBMITTER: Wang J

PROVIDER: S-EPMC6817462 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Hepatocyte Nuclear Factor 3β Plays a Suppressive Role in Colorectal Cancer Progression.

Wang Juan J Lu Hao H Wang Wei W Zheng Nanxin N Wang Yi Y Hu Zhiqian Z Ji Gang G

Frontiers in oncology 20191022

<b>Background and Objective:</b> Hepatocyte nuclear factor 3β (HNF3β) is a key transcription factor in the development of the gastrointestinal tract. However, only few studies have examined its' expression, function and potential clinical significance in colorectal cancer tumorigenesis and progression. <b>Methods:</b> HNF3β expression in colorectal cancer tissue samples of 174 patients was assessed by immunohistochemistry. The results were analyzed with respect to patients' clinicopathological c ...[more]

PMID: 31696055

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Project description:BackgroundColorectal cancer (CRC) is one of the most common cancers worldwide; it is the fourth leading cause of death in the world and the third in Brazil. Mutations in the APC, DCC, KRAS and TP53 genes have been associated with the progression of sporadic CRC, occurring at defined pathological stages of the tumor progression and consequently modulating several genes in the corresponding signaling pathways. Therefore, the identification of gene signatures that occur at each stage during the CRC progression is critical and can present an impact on the diagnosis and prognosis of the patient. In this study, our main goal was to determine these signatures, by evaluating the gene expression of paired colorectal adenoma and adenocarcinoma samples to identify novel genetic markers in association to the adenoma-adenocarcinoma stage transition.MethodsTen paired adenoma and adenocarcinoma colorectal samples were subjected to microarray gene expression analysis. In addition, mutations in APC, KRAS and TP53 genes were investigated by DNA sequencing in paired samples of adenoma, adenocarcinoma, normal tissue, and peripheral blood from ten patients.ResultsGene expression analysis revealed a signature of 689 differentially expressed genes (DEG) (fold-change>?2, p<?0.05), between the adenoma and adenocarcinoma paired samples analyzed. Gene pathway analysis using the 689 DEG identified important cancer pathways such as remodeling of the extracellular matrix and epithelial-mesenchymal transition. Among these DEG, the ETV4 stood out as one of the most expressed in the adenocarcinoma samples, further confirmed in the adenocarcinoma set of samples from the TCGA database. Subsequent in vitro siRNA assays against ETV4 resulted in the decrease of cell proliferation, colony formation and cell migration in the HT29 and SW480 colorectal cell lines. DNA sequencing analysis revealed KRAS and TP53 gene pathogenic mutations, exclusively in the adenocarcinomas samples.ConclusionOur study identified a set of genes with high potential to be used as biomarkers in CRC, with a special emphasis on the ETV4 gene, which demonstrated involvement in proliferation and migration.

Dataset Information

Hepatocyte Nuclear Factor 3? Plays a Suppressive Role in Colorectal Cancer Progression.

Publications

Hepatocyte Nuclear Factor 3β Plays a Suppressive Role in Colorectal Cancer Progression.

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