HNF1α and CDX2 transcriptional factors bind to cadherin‐17 (CDH17) gene promoter and modulate its expression in hepatocellular carcinoma

Abstract

Cadherin-17 (CDH17) belongs to the cell adhesion cadherin family with a prominent role in tumorigenesis. It is highly expressed in human hepatocellular carcinoma (HCC) and is proposed to be a biomarker and therapeutic molecule for liver malignancy. The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC. A 1-kb upstream sequence of CDH17 gene was cloned and the promoter activity was studied by luciferase reporter assay. By bioinformatics analysis, deletion and mutation assays, and chromatin immunoprecipitation studies, we identified hepatic nuclear factor 1α (HNF1α) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L). A consistent down-regulation of CDH17 and the two transcriptional activators (HNF1α and CDX2) expression was found in the liver of mouse during development, as well as in human liver cancer cells with less metastatic potential. Suppression of HNF1α and CDX2 expression by small interfering RNA (siRNA) significantly down-regulated expressions of CDH17 and its downstream target cyclin D1 and the viability of HCC cells in vitro. In summary, we identified the minimal promoter region of CDH17 that is regulated by HNF1α and CDX2 transcriptional factors. The present findings enhance our understanding on the regulatory mechanisms of CDH17 oncogene in HCC, and may shed new insights into targeting CDH17 expression as potential therapeutic intervention for cancer treatment.

HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties

“…Interestingly, HNF1A, a P2 cohort gene itself (Figure 1E,F), had predicted binding sites in the ±5000 regions (from start of transcription) of 17/50 of the enriched genes, and due to its stringent consensus sequence (DGTTAATNATTAAC) was the most highly ranked common transcription factor by Z-score (17.895). Of these 50 genes, HNF1A is known to positively regulate cohort genes HNF4A (Boj et al, 2001), NR5A2 (Molero et al, 2012), CDH17 (Zhu et al, 2010), IGFBP1 (Babajko et al, 1993; Powell and Suwanichkul, 1993), and DPP4 (Gu et al, 2008). Interestingly, genome-wide association (GWA) studies have recently identified certain single nucleotide polymorphisms (SNPs) in the HNF1A locus as risk factors for developing PDA (Pierce and Ahsan, 2011; Li et al, 2012; Wei et al, 2012), although the mechanism by which these SNPs exert their influence is currently unknown.…”

Liver-Intestine Cadherin Expression Is Associated with Intestinal Differentiation and Carcinogenesis in Intraductal Papillary Mucinous Neoplasm

“…Colocalization of CDX2 and LI cadherin was seen in intestinal metaplasia and adenocarcinoma of the stomach [27] . LI cadherin might be regulated by a complex regulatory mechanism of not only CDX2 but also human hepatocyte nuclear factor-1 ␣ (HNF1 ␣ ), metal-responsive transcription factor-1 (MTF-1), and placental growth factor (PIGF) as described in previous reports [20,28] .…”

Proinflammatory Homeobox Gene, ISX, Regulates Tumor Growth and Survival in Hepatocellular Carcinoma

“…Homeobox genes, essential regulatory transcription factors for multiple body plan development (10), have been found to be deregulated in many malignancies and are thought to be potential oncogenes (11). Few homeobox genes have been found to be involved in HCC development, excluding Hox, Prox1, and CDX2; however, most of them are expressed both in normal and in tumor cells and are thought to act as tumor suppressors in the liver (22)(23)(24). In this study, we found Isx, in particular, ectopically expressed in tumor cells of HCC tumor mass, but not normal cells, and highly correlated to cyclin D1 expression in HCC tumor cells.…”