Abstract
Hepatocyte nuclear factor 1 beta (HNF1B) is a tissue specific transcription factor, which seems to play an important role in the carcinogenesis of several tumors. In our study we focused on analyzing HNF1B in prostate carcinoma (PC) and adenomyomatous hyperplasia (AH), as well as its possible relation to the upstream gene EZH2 and downstream gene ECI2. The results of our study showed that on an immunohistochemical level, the expression of HNF1B was low in PC, did not differ between PC and AH, and did not correlate with any clinical outcomes. In PC, mutations of HNF1B gene were rare, but the methylation of its promotor was a common finding and was positively correlated with Gleason score and stage. The relationship between HNF1B and EZH2/ECI2 was equivocal, but EZH2 and ECI2 were positively correlated on both mRNA and protein level. The expression of EZH2 was associated with poor prognosis. ECI2 did not correlate with any clinical outcomes. Our results support the oncosuppressive role of HNF1B in PC, which may be silenced by promotor methylation and other mechanisms, but not by gene mutation. The high expression of EZH2 (especially) and ECI2 in PC seems to be a potential therapeutic target.
Highlights
Hepatocyte nuclear factor 1 beta (HNF1B) is a tissue specific transcription factor, which seems to play an important role in the carcinogenesis of several tumors
The immunohistochemical analysis of all three markers including HNF1B, enhancer of zeste homolog 2 (EZH2) and enoyl-coenzyme A (CoA)-(Δ) isomerase 2 (ECI2) was performed on the total of 101 prostate carcinoma (PC) and 18 adenomyomatous hyperplasia (AH) samples
Due to the requirement of high-quality genetic material, it was possible to carry out the DNA methylation analysis and mRNA expression analysis (HNF1B, EZH2, ECI2) only on the frozen tissue (FT) samples
Summary
Hepatocyte nuclear factor 1 beta (HNF1B) is a tissue specific transcription factor, which seems to play an important role in the carcinogenesis of several tumors. HNF1B is commonly inactivated in prostate cancer, especially due to HNF1B promoter methylation, which occurs in about 50% of cases[11] Another recently suggested possible mechanisms of HNF1B inactivation is the effect of the enhancer of zeste homolog 2 (EZH2), the overexpression of which has been suggested to downregulate the expression of HNF1B12,13. HNF1B plays a role in glucose metabolism, influencing both insulin secretion and renal glucose reabsorption, which is one of the key mechanisms in selective advantage of several tumor types[30] It has been shown in an animal model that the downregulation of HNF1B protein levels during tumor progression is associated with the upregulation of enoyl-CoA-(Δ) isomerase 2 (ECI2), which is one of the possible downstream targets of H NF1B31
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