HNF4α: a new biomarker in colon cancer?

Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide with 50,000 deaths related to CRC annually in the USA alone. Early detection (Duke’s stage A) predicts good survival (>90%) among CRC patients while the involvement of lymph nodes (stage C) or metastases (stage D) generally predicts survival below 50 and 10%, respectively. This highlights the need to identify prognostic biomarkers of early stage CRC as well as the need for more effective treatments at later stages. Here, we discuss the growing interest of HNF4α in CRC, as well as its potential as a biomarker for prognosis, susceptibility and treatment of this deadly disease. HNF4α is a highly conserved member of the nuclear receptor superfamily of ligand-dependent transcription factors. It is expressed in the liver, pancreas, kidney, stomach, small intestine and colon, where it regulates many important aspects of epithelial cell morphogenesis and function. Nine different isoforms of HNF4α produced by alternate promoter usage and splicing have been identified thus far. Isoforms HNF4α1–3 are derived from the P1 promoter (P1-HNF4α), whereas HNF4α7–12 are derived from the P2 promoter (P2-HNF4α). The P1- and P2-driven proteins differ by approximately 16–29 amino acids in their N-terminal domain, which encodes an important activation function [101]. HNF4α is best known for its role in the liver and pancreas, including an inherited form of Type 2 diabetes referred to as MODY1, although it is increasingly being linked to liver and colon cancer [1–7]. Expression of P1- and P2-driven HNF4α in adult and embryonic liver, respectively, is essential for hepatocyte function and liver development [101]. Not surprisingly, loss of HNF4α leads to dedifferentiation of hepatocytes; it also leads to a switch from slow-growing to rapidly proliferating aggressive hepatocellular carcinoma (HCC) [1]. Recently HNF4α was identified as a central player in an inflammatory feedback loop involving IL-6 and miRNAs that leads to a decrease in HNF4A expression and an increase in HCC occurence [2]. While such reports do not distinguish between the P1- and P2-HNF4α isoforms, other studies have shown that P1-HNF4α expression is reduced in human and mouse HCC tissues while P2-HNF4α expression is aberrantly activated [6,8]. Taken together, these findings suggest that P1-HNF4α acts as a tumor suppressor in hepatocytes. However, the precise role of P2-HNF4α in HCC, and other cancers, remains to be determined.

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