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m6A-Dependent ITIH1 Regulated by TGF-β Acts as a Target for Hepatocellular Carcinoma Progression
Zhibin Liao1,2, Hongwei Zhang1,2, Furong Liu1,2
1Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
Abstract:
Both the transforming growth factor beta (TGF-β) signaling pathway and N6-methyladenosine (m6A) modification for mRNA play an important role in hepatocellular carcinoma (HCC) progression. However, the relationship between TGF-β and m6A in hepatocellular carcinoma (HCC) remains unclear. Here, it is found that TGF-β can promote the liquid phase separation of METTL3, which further leads to the reduction of mRNA stability of ITIH1. As a secreted protein, ITIH1 can act as a ligand of integrin α5β1 to antagonize fibronectin, induce the inhibition of focal adhesion kinase signaling pathway, and inhibit the progression of HCC. In the preclinical model (mouse model, patient-derived organoid, patient-derived xenografts), purified recombinant ITIH1 (r-ITIH1) protein can be targeted for HCC. More importantly, r-ITIH1 can play a synergistic role in targeting HCC with TGF-β inhibitor. The downstream ITIH1 regulatory mechanism of TGF-β and m6A modification is revealed, and ITIH1 can be translational as a potential target for HCC.
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