Author:
Hoshino Kouki,Nakazawa Seshiru,Yokobori Takehiko,Hagiwara Kei,Ishii Norihiro,Tsukagoshi Mariko,Igarashi Takamichi,Araki Kenichiro,Harimoto Norifumi,Tokunaga Fuminori,Shirabe Ken
Abstract
AbstractRNF31 is a multifunctional RING finger protein implicated in various inflammatory diseases and cancers. It functions as a core component of the linear ubiquitin chain assembly complex (LUBAC), which activates the nuclear factor kappaB (NF-κB) pathway via the generation of the Met1-linked linear ubiquitin chain. We aimed to clarify the role of RNF31 in the pathogenesis of hepatocellular carcinoma (HCC) and its relevance as a therapeutic target. High RNF31 expression in HCC, assessed by both immunohistochemistry and mRNA levels, was related to worse survival rates among patients with HCC. In vitro experiments showed that RNF31 knockdown in HCC cell lines led to decreased cell proliferation and invasion, as well as suppression of tumor necrosis factor (TNF)-α-induced NF-κB activation. Treatment with HOIPIN-8, a specific LUBAC inhibitor that suppresses RNF31 ubiquitin ligase (E3) activity, showed similar effects, resulting in decreased cell proliferation and invasion. Our clinical and in vitro data showed that RNF31 is a prognostic factor for HCC that promotes tumor aggressiveness via NF-κB activation.
Funder
Japan Society for the Promotion of Science
Takeda Science Foundation
YOKOYAMA Foundation for Clinical Pharmacology
Publisher
Springer Science and Business Media LLC