Treatment-damaged hepatocellular carcinoma promotes activities of hepatic stellate cells and fibrosis through GDF15

Experimental Cell Research
Gang DongRong-Xin Chen

Abstract

The aim of this study was to investigate whether treatment-damaged hepatocellular carcinoma (HCC) would accelerate liver cirrhosis through promoting the activities of hepatic stellate cells (HSCs). HCC cells were exposed to chemotherapeutic agent or hypoxia to mimic the transarterial chemoembolization (TACE)-like treatment. Growth differentiation factor 15 (GDF15) expression was increased in cisplatin- or hypoxia-treated HCC cells. Treatment-induced GDF15 increase in HCC cells was mediated by p38MAPK, JNK, ERK1/2 activation. GDF15 from treatment-damaged HCC cells enhanced the proliferation and collagen synthesis of HSCs through ERK1/2- and Smad3-dependent pathways. Metformin significantly reduced the GDF15 production from treatment-damaged HCC cells by targeting JNK. The use of metformin could attenuate the in vivo fibrotic activities of HSCs promoted by treatment-damaged HCC cells and inhibit GDF15 expression. In conclusion, treatment-damaged HCC accelerates fibrosis by promoting the activities of HSCs via GDF15 secretion, which could be reversed by metformin. This provides a potential therapeutic target for alleviating TACE-aggravated liver cirrhosis.

Citations

May 12, 2019·Critical Reviews in Clinical Laboratory Sciences·Stéphanie DesmedtMarijn M Speeckaert
Feb 6, 2020·International Journal of Cancer. Journal International Du Cancer·Qi RuanXiaowen Liang
Aug 28, 2020·Frontiers in Cell and Developmental Biology·Anna E BarryHien Dang
Dec 16, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zhaoyan KongYuanrong Cheng
Apr 20, 2020·Experimental Cell Research·Yasuhiro TakenouchiYasuo Okamoto
Aug 28, 2021·Cells·Ho-Yeop LeeHyon-Seung Yi

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