TM4SF5-mediated liver malignancy involves NK cell exhaustion-like phenotypes.

Autor: Sun H; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea., Kim E; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea., Ryu J; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea., Lee H; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea., Shin EA; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea., Lee M; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea., Lee H; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea., Lee JH; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea., Yoon JH; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea., Song DG; Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung-si, Gangwon-do, 25451, Republic of Korea., Kim S; Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, 34141, Republic of Korea., Lee JW; Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. jwl@snu.ac.kr.; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. jwl@snu.ac.kr.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2021 Dec 18; Vol. 79 (1), pp. 49. Date of Electronic Publication: 2021 Dec 18.
DOI: 10.1007/s00018-021-04051-x
Abstrakt: Aberrant extracellular matrix and immune cell alterations within the tumor microenvironment promote the pathological progression of liver carcinogenesis. Although transmembrane 4 L six family member 5 (TM4SF5) is involved in liver fibrosis and cancer, its mechanism avoiding immune surveillance during carcinogenesis remains unknown. We investigated how TM4SF5-mediated signaling caused immune evasion using in vitro primary cells and in vivo liver tissues from genetic or chemically induced mouse models. TM4SF5-transgenic and diethylnitrosamine (DEN)-induced liver cancer mouse models exhibited fibrotic and cancerous livers, respectively, with enhanced TM4SF5, pY 705 STAT3, collagen I, and laminin γ2 levels. These TM4SF5-mediated effects were abolished by TM4SF5 inhibitor, 4'-(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC). TM4SF5-dependent tumorigenesis involved natural killer (NK) cell exhaustion-like phenotypes including the reduction of NK cell number or function, which were blocked with TSAHC treatment. TM4SF5 expression in cancer cells downregulated stimulatory ligands and receptors for NK cell cytotoxicity, including SLAMF6, SLAMF7, MICA/B, and others. TM4SF5 suppression or inhibition reduced STAT3 signaling activity and recovered the receptor levels and NK cell surveillance, leading to reduced fibrotic and cancerous phenotypes, and longer survival. Altogether, these findings suggest that TM4SF5-mediated STAT3 activity for extracellular matrix modulation is involved in the progression of liver disease to HCC and that TM4SF5 appears to suppress NK cells during liver carcinogenesis.
(© 2021. The Author(s).)
Databáze: MEDLINE
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