HNF1B expression regulates ECI2 gene expression, potentially serving a role in prostate cancer progression

Abstract

Prostate cancer is the most common form of cancer in men, with increased incidence rates observed in older individuals. Prostate cancer is primarily driven via activation of the androgen receptor (AR), the principal transcriptional factor governing prostate cancer cellular programming and its associated metabolism. One of the downstream targets of AR is hepatocyte nuclear factor-1β (HNF1B), an important oncogenic transcription factor in prostate cancer. In the present study, the regulatory role of HNF1B in enoyl-CoA-(Δ) isomerase 2 (ECI2) expression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model was investigated. Using this model, tumor progression and associated pathological alterations at 12, 18 and 24 weeks were analyzed. Histological sectioning revealed pathological alterations over time, including thickening of glandular epithelial cells (12 weeks), increases in cellular proliferation (18 weeks), and extensive thickening and hardening of the tissue layer (24 weeks). Expression levels of HNF1B and ECI2 proteins were validated by immunohistochemistry and western blotting at different stages of prostate cancer development. HNF1B and ECI2 exhibited minimal differences in protein expression at 12 weeks in TRAMP+ mice. However, by 18 weeks, TRAMP+ mice exhibited multi-fold increases in HNF1B expression levels, along with downregulation of ECI2. These effects were reversed at 24 weeks, indicating an important time-dependent regulation of gene expression. Taken together, these results demonstrated that upon tumor progression, the initial tumor-protective effect of HNF1B is lost along with downregulated expression of HNF1B and increased expression of ECI2.

HNF1B, EZH2 and ECI2 in prostate carcinoma. Molecular, immunohistochemical and clinico-pathological study

“…The downstream interaction of HNF1B is currently poorly understood, but based on the animal model it has been suggested that the downregulation of HNF1B during tumor progression is associated with the upregulation of enoyl-CoA-(Δ) isomerase 2 (ECI2) protein levels, which is one of the possible downstream targets of HNF1B 31 . ECI2 represents one of the androgen receptor (AR) target genes 32,57 .…”

“…In a mouse model, the authors compare HNF1B and ECI2 protein expression at different stages of prostate cancer development and concluded that during tumor progression, the protective effect of HNF1B is lost, and that is associated with an increased expression of ECI2 31 . The results of our study, compared to the only two previous studies concerning ECI2 in prostate cancer, similarly found an overexpression of ECI2 in the PC group, which was statistically significant in contrast to the low expression in AH samples.…”

“…HNF1B also 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 . Recently, 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 HNF1B 31 .…”

“…Both HNF1B and ECI2 are assumed to be downstream targets of AR, which is a major driver in prostate cancer 31 , 32 . However, the specific interaction between HNF1B and ECI2 is uncertain, but according to recent data, the increased gene expression of ECI2 may promote prostate cancer growth 32 .…”

Integrative Analysis of HNF1B mRNA in Human Cancers Based on Data Mining

“…HNF1B is a member of the HNF family, participates in regulating the metabolism of lipids, carbohydrates and proteins, and plays an important role in regulating hepatocyte differentiation and liver development 20 . Recent studies have shown that HNF1B has a significant correlation with the occurrence and development of various tumors, such as prostate cancer and pancreatic cancer 21 , 22 . In this study, we found that the expression of HNF1B was upregulated at different levels in BLCA, CHOL, KIRP, LIHC, STAD, THCA, and UCEC and downregulated in COAD, GBM, KICH, KIRC, and LUSC.…”