Abstract B40: Derangement HNF4α gene expression as a candidate marker of hepatocellular carcinoma progression

• Published in: Clinical cancer research 2010-04, Vol.16 (7_Supplement), p.B40-B40
• Main Authors: Shavochkina, Daria A., Fleishman, Daria I., Morozova, Olga V., Chuchuev, Evgeniy S., Patyutko, Yuriy I., Lazarevich, Natalia L.
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.TCME10-B40

Hepatocellular carcinoma (HCC) is one of the world's most common cancers. The development of malignant phenotype is considered to be a multistep process that results from the accumulation of genetic alterations. Mechanisms of epithelial carcinogenesis are determined by the specific properties of tumor progenitor tissue. According to our investigations, HCC progression is associated with the dysfunction of hepatocyte nuclear factors (HNFs), which control liver-specific gene expression, and particularly HNF4α, a nuclear receptor playing a key role in hepatic differentiation. This gene is transcribed from two distinct promoters, which activity results in producing two groups of isoforms and reflects the level of cell differentiation. HNF4αP2 isoforms are synthesized in embryonic liver and normally disappear after birth, while HNF4αP1 become dominant in mature hepatocytes. Reexpression of HNF4αP1 reversed the malignant phenotype of dedifferentiated mouse HCC variants. Studies on the collection of chemically induced mouse HCCs of independent origin revealed strict correlation of HNF4α expression with tumor differentiation state. Using semiquantitative RT-PCR we have analyzed the expression of 46 genes in 21 samples of human HCCs. 17 of studied cases were not associated with Hepatitis viruses infections, while 4 of patients were infected with hepatitis B virus. The most frequent event revealed in HCC samples compared to corresponding non-tumor tissues was the complete loss (in 7 of 17 non-hepatitis HCCs) or significant decrease (in 5 of 17 non-hepatitis HCCs) of HNF4αP1 transcription. Decrease of HNF4α expression appeared to be a poor prognostic factor: patients with highly expressed HNF4αP1 had 100% 3-years survival, and 83% of them didn't have any disease progression, while only 33% of patients with low HNF4αP1 expression showed no disease progression. HCCs which were associated with hepatitis infection didn't show relevant alterations in HNF4αP1 expression. We suppose that hepatitis-associated hepatocarcinogenesis might develop through HNF4α1-independent mechanism. Intracellular localization and protein expression level of HNF4α isoforms on the paraffine sections of human HCCs was investigated immunohistochemically using specific mouse monoclonal antibodies for HNF4αP1 (K9218; R&D systems; 1:6000) or HNF4αP2 (H6939; R&D systems; 1:3000) groups of isoforms. HNF4α isoforms immunoreactivity was detectable in all studied tumors except severely dedifferentiated va