Hepatocyte nuclear factor 4α multiple isoforms, their functions, and their interactomes.

Hepatocyte nuclear factor 4-alpha (HNF4α) is a master regulator gene belonging to the nuclear receptor superfamily and is involved in regulating a wide range of critical biological processes in different organs. Structurally, the HNF4A locus is organized into two independent promoters and is subjected to alternative splicing to produce twelve distinct isoforms. However, little is known about the biological impact of each isoform and the mechanisms by which they regulate transcription. Proteomic analyses have led to the identification of proteins that interact with specific HNF4α isoforms. The identification and validation of these interactions and their roles in the co-regulation of targeted gene expression are essential to better understand the role of this transcription factor in different biological processes and pathologies. This review addresses the discoveries of different HNF4α isoforms and the main functions of the P1 and P2 isoform subgroups. It also provides information on the most recent focus areas in research on the nature and function of proteins associated with each of the isoforms in some biological contexts.

KRAS Promoter Methylation Status and miR-18a-3p and miR-143 Expression in Patients With Wild-type KRAS Gene in Colorectal Cancer.

BACKGROUND/AIM: Although some mutations of KRAS proto-oncogene, GTPase (KRAS) have been associated with the prognosis and therapeutic management of colorectal cancer (CRC), the epigenetic mechanisms (DNA methylation and microRNA expression) that regulate wild-type KRAS expression in patients with CRC are poorly known. The aim of this study was to establish whether there is a relationship between the expression of the wild-type KRAS gene, the methylation status of its distal promoter, and miR-143 and miR-18a-3p levels in samples of sporadic CRC. PATIENTS AND METHODS: A total of 51 cases of sporadic CRC with wild-type KRAS were analyzed. The expression levels of KRAS mRNA, miR-18a-3p, miR-143, and KRAS protein, as well as methylation in the distal promoter of the KRAS gene were evaluated. RESULTS: In the analyzed cases, KRAS mRNA expression was detected in 51.1%; wild-type KRAS protein was found in the membrane in 31.4% and in the cytoplasm in 98% of cases. An inverse relationship of marginal significance was observed between miR-18a-3p and KRAS protein expression in the cytoplasm (odds ratio=0.14, 95% confidence interval=0.012-1.092; p=0.08). The methylation status of the distal promoter of KRAS at four CpG islands was analyzed in 30 cases (58.8%): partial methylation of the four CpG islands evaluated was observed in two cases (6.7%). In these cases, KRAS protein expression was not evidenced at the membrane level; miR-18a-3p expression was not detected either but high expression of miR-143 was observed. CONCLUSION: No association was found between the expression levels of KRAS mRNA, miR-18a-3p, miR-143 and methylation status. Methylation status was detected with low frequency, thus being the first report of methylation in wild-type KRAS.