Abstract 5460: Effects of nuclear receptor HNF4α repression in human pancreatic ductal adenocarcinoma cells.
Authors: Chesnokov Mikhail S. , Gorev Artem D. , Lazarevich Natalia L. 
Published: August 2014

HNF4α transcription factor is an orphan nuclear receptor that belongs to the hepatocyte nuclear factors (HNFs) group. HNFs are essential for differentiation and functionality of liver, pancreas, intestine and kidney during ontogenesis.

A number of studies revealed that HNF4α is a key regulator of HNFs transcription control network in hepatocytes. Derangement of HNF4α expression is crucial for the development and progression of hepatocellular carcinoma (HCC); restoration of HNF4α expression in dedifferentiated HCC cells results in partial reversion of their malignant properties. Also HNF4α acts as a tumor suppressor in kidney and intestinal epithelium cells, but it's functions in pancreatic cells are very poorly investigated.

HNF4α expression is regulated by two independent promoters, P1 and P2. Resulting HNF4αP1 and HNF4αP2 groups of isoforms differ by distinct expression pattern in various epithelial tissues and trans-activation ability. In normal pancreatic tissue HNF4αP2 isoforms are predominant. We have shown that development of pancreatic ductal adenocarcinoma (PDAC), the most aggressive type of pancreatic tumors, is accompanied by derangement of HNF4α expression. Similar patterns of HNF4α isoforms expression were described in PDAC cell lines and clinical samples of pancreatic tumor tissue. Highly differentiated PDAC cells are characterized by retaining of HNF4αP2 isoforms expression, whereas extrinsic HNF4αP1 isoforms are activated in moderately differentiated cells and poorly differentiated cells lack the expression of both groups of HNF4α isoforms. To find out the role of HNF4α deregulation in PDAC progression we have studied the biological impact of HNF4α knock-down in human moderately differentiated PDAC cell line AsPC1.

Using lentiviral infection we have obtained AsPC1 cell cultures constitutively expressing shRNAs to HNF4α (AsPC1-sh cells). HNF4α downregulation in AsPC1-sh cells resulted in diminished expression of HNF1α, direct target gene of HNF4α and important regulator of pancreatic cells differentiation. Cells with repressed HNF4α expression demonstrated drastic increase in their ability for directional migration and induction of N-cadherin expression. On the other hand, AsPC1-sh cells exhibit lower colony formation ability and significant decrease in proliferation and DNA synthesis.

These results indicate that deregulation of HNF4α expression is frequent event in pancreatic carcinogenesis. The repression of HNF4α in PDAC cells exerts complex alterations of biological properties of PDAC cells, which include both promotion and attenuation of certain cell characteristics that determine the degree of malignant cell phenotype manifestation.

The work was partly supported by grants from RFBR (13-04-02080) and grant from Russian ministry of education and science (№ 8066, code 2012-1.1-12-000-1002-064).

Citation Format: Mikhail S. Chesnokov, Artem D. Gorev, Natalia L. Lazarevich. Effects of nuclear receptor HNF4α repression in human pancreatic ductal adenocarcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5460. doi:10.1158/1538-7445.AM2013-5460