Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4α in the pathogenesis of human cancer

Abstract

Hepatocyte nuclear factor-4alpha (HNF4alpha) exists in multiple isoforms that are generated by alternative promoter (P1 and P2) usage and splicing. Here we establish monoclonal antibodies (mAbs) for detecting P1 and P2 promoter-driven HNF4alpha, and evaluate their expression in normal adult human tissues and surgically resected carcinomas of different origins. Using immunohistochemical analysis, we demonstrate that, while P1 promoter-driven HNF4alpha is expressed in hepatocytes, small intestine, colon, kidney and epididymis, P2 promoter-driven HNF4alpha is expressed in bile duct, pancreas, stomach, small intestine, colon and epididymis. Altered expression patterns of P1 and P2 promoter-driven HNF4alpha were observed in gastric, hepatocellular and colorectal carcinomas. HNF4alpha was expressed in lung metastases from renal cell, hepatocellular and colorectal carcinoma but was not observed in lung tumours. The P1 and P2 promoter-driven HNF4alpha expression pattern of tumour metastases correlated with the primary site of origin. P1 promoter-driven HNF4alpha was also found in intestinal metaplasia of the stomach. These data provide evidence for the tissue distribution of P1 and P2 promoter-driven HNF4alpha at the protein level and suggest that HNF4alpha may be a novel diagnostic marker for metastases of unknown primary. We propose that the dysregulation of alternative promoter usage of HNF4alpha is associated with the pathogenesis of certain cancers.

The expression pattern of nuclear receptors during cerebellar development

“…However, in control experiments, they were detected in other tissues in which each was already known to be expressed (Sladek et al, 1990;Zennaro et al, 1997;Zineb et al, 1998;Tulachan et al, 2003;Jeyasuria et al, 2004;Tanaka et al, 2006). These results suggest that they are not expressed or expressed at a very low level in the cerebellum at this stage of development.…”

The Diabetic Phenotype in HNF4A Mutation Carriers Is Moderated By the Expression of HNF4A Isoforms From the P1 Promoter During Fetal Development

“…Although two studies report the absence of P1 transcripts (27,32), one report suggests the expression of transcripts derived from the P1 promoter (33). However, it is noteworthy that the only study to examine isoformspecific HNF4A expression at the protein level detected only P2-derived isoforms in adult pancreas (35).…”

Overexpression of hepatocyte nuclear factor 4α in human mesenchymal stem cells suppresses hepatocellular carcinoma development through Wnt/β-catenin signaling pathway downregulation

“…The UC-MSCs were prepared as previously described. The mesenchymal tissue was diced into cubes of approximately 1 cm 3 . Following the removal of the supernatant fraction, the precipitate was washed with DMEM/F12 (Gibco) and centrifuged at 250£g for 5 min.…”

“…1 Hepatocyte nuclear factor 4a (HNF4a) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis (HCC). 2,3 We have previously demonstrated that overexpression of HNF4a activates various hepatic-specific genes and enhances MSC differentiation.…”