Sun, H. Kim, E. Ryu, J. Lee, H. Shin, E.-A. Lee, M. Lee, H. Lee, J.-H. Yoon, J.-H. Song, D.-G. Kim, S. Lee, J.W. 2024-01-19T13:01:54Z 2024-01-19T13:01:54Z 2022-02-17 2022-01 1420-682X https://pubs.kist.re.kr/handle/201004/115864 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, pY705STAT3, 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). English Birkhauser Verlag TM4SF5-mediated liver malignancy involves NK cell exhaustion-like phenotypes Article 10.1007/s00018-021-04051-x 1 Cellular and Molecular Life Sciences, v.79, no.1 Cellular and Molecular Life Sciences 79 1 Y scie scopus 000731391900003 2-s2.0-85121356989 Biochemistry & Molecular Biology Cell Biology Biochemistry & Molecular Biology Cell Biology Article EPITHELIAL-MESENCHYMAL TRANSITION MICROTUBULE-ORGANIZING CENTER NATURAL-KILLER-CELLS CROSS-TALK TM4SF5 EXPRESSION INHIBITION STAT3 POLARIZATION PERFORIN Immune checkpoint L6 family member Liver cancer NK cell immune therapy Signal transduction