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mA 依赖性 ITIH1 通过 TGF-β 调控可作为肝细胞癌进展的靶点。

mA-Dependent ITIH1 Regulated by TGF-β Acts as a Target for Hepatocellular Carcinoma Progression.

机构信息

Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.

Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, 430030, China.

出版信息

Adv Sci (Weinh). 2024 Nov;11(42):e2401013. doi: 10.1002/advs.202401013. Epub 2024 Sep 5.

DOI:10.1002/advs.202401013
PMID:39234824
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11558142/
Abstract

Both the transforming growth factor beta (TGF-β) signaling pathway and N6-methyladenosine (mA) modification for mRNA play an important role in hepatocellular carcinoma (HCC) progression. However, the relationship between TGF-β and mA 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 mA modification is revealed, and ITIH1 can be translational as a potential target for HCC.

摘要

转化生长因子-β（TGF-β）信号通路和 mRNA 的 N6-甲基腺苷（m6A）修饰均在肝细胞癌（HCC）进展中发挥重要作用。然而，TGF-β与 HCC 中的 mA 之间的关系尚不清楚。本研究发现，TGF-β 可促进 METTL3 的液-液相分离，进而导致 ITIH1 的 mRNA 稳定性降低。作为一种分泌蛋白，ITIH1 可作为整合素α5β1 的配体，拮抗纤维连接蛋白，诱导粘着斑激酶信号通路抑制，从而抑制 HCC 的进展。在临床前模型（小鼠模型、患者来源的类器官、患者来源的异种移植物）中，纯化的重组 ITIH1（r-ITIH1）蛋白可用于靶向 HCC。更重要的是，r-ITIH1 可与 TGF-β 抑制剂协同靶向 HCC。揭示了 TGF-β和 mA 修饰的下游 ITIH1 调控机制，ITIH1 可作为 HCC 的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/2c3e42998495/ADVS-11-2401013-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/f4ff137eaf9e/ADVS-11-2401013-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/ff6e66e2b5f4/ADVS-11-2401013-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/14a9d9e4ff03/ADVS-11-2401013-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/2c3e42998495/ADVS-11-2401013-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/f4ff137eaf9e/ADVS-11-2401013-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/41b3cff9e12f/ADVS-11-2401013-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/add708378fa7/ADVS-11-2401013-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/0cf25506a1cb/ADVS-11-2401013-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/ff6e66e2b5f4/ADVS-11-2401013-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/14a9d9e4ff03/ADVS-11-2401013-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1d/11558142/2c3e42998495/ADVS-11-2401013-g008.jpg

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