Involvement of MAFB and MAFF in Retinoid-Mediated Suppression of Hepatocellular Carcinoma Invasion.

Hiroyuki Tsuchiya,Seiya Oura

doi:10.3390/ijms19051450

Abstract

Retinoids exert antitumor effects through the retinoic acid receptor α (RARα). In the present study, we sought to identify the factors involved in the RARα-mediated transcriptional regulation of the tumor suppressor gene and the tissue factor pathway inhibitor 2 (TFPI2) in hepatocellular carcinoma (HCC). All-trans-retinoic acid (ATRA) was used in the in vitro experiments. Cell invasiveness was measured using trans-well invasion assay. ATRA significantly increased TFPI2 expression through RARα in a human HCC cell line known as HuH7. TFPI2 was vital in the ATRA-mediated suppression of HuH7 cell invasion. The musculo-aponeurotic fibrosarcoma oncogene homolog B (MAFB) significantly enhanced the activation of the TFPI2 promoter via RARα while MAFF inhibited it. The knockdown of RARα or MAFB counteracted the ATRA-mediated suppression of HuH7 cell invasion while the knockdown of MAFF inhibited the invasion. TFPI2 expression in HCC tissues was significantly downregulated possibly due to the decreased expression of RARβ and MAFB. Patients with HCC expressing low MAFB and high MAFF levels showed the shortest disease-free survival time. These results suggest that MAFB and MAFF play critical roles in the antitumor effects of retinoids by regulating the expression of retinoid target genes such as TFPI2 and can be promising for developing therapies to combat HCC invasion.

Highlights

Preclinical studies have shown that retinoids possess anticancer effects against different cancer cell lines in vitro [1,2,3]
They are divided into two groups based on structural characteristics including large musculoaponeurotic fibrosarcoma (MAF), which involve c-MAF, MAFA, and musculo-aponeurotic fibrosarcoma oncogene homolog B (MAFB), and small MAFs, which include MAFF, MAFG, and MAFK
MAFG was recently revealed as a transcriptional repressor of bile acid synthesis and metabolism [25]

Summary

Introduction

Preclinical studies have shown that retinoids possess anticancer effects against different cancer cell lines in vitro [1,2,3]. It was demonstrated that retinoids reduced cancer risk by 70%. The retinoic acid receptor α (RARα) is a central mediator of pleiotropic actions of retinoids. Many other factors take part in retinoid action by modulating the transactivating functions of RARα. A nuclear receptor co-repressor and a short heterodimer partner bind to RARα and suppress its function [6,7] while SP1 and the B-cell translocation gene 1 activate RARα via direct interaction [8,9]. Since retinoids produce severe side effects including tetracarcinogenesis, mucocutaneous cytotoxicity, and hypertriglyceridemia [10], elucidating the mechanism underlying retinoid-facilitated transcriptional regulation is crucial in developing next-generation retinoid-acting drugs with an improved specificity

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Conclusion