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.
Cell Mol Life Sci. 2021 Dec 18;79(1):49. doi: 10.1007/s00018-021-04051-x.
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, pYSTAT3, 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.
细胞外基质和肿瘤微环境中的免疫细胞改变促进肝癌的病理进展。虽然跨膜 4 L 六家族成员 5(TM4SF5)参与肝纤维化和癌症,但它在致癌过程中逃避免疫监视的机制尚不清楚。我们使用体外原代细胞和遗传或化学诱导的小鼠模型的体内肝组织研究了 TM4SF5 介导的信号转导如何引起免疫逃逸。TM4SF5 转基因和二乙基亚硝胺(DEN)诱导的肝癌小鼠模型分别表现出纤维化和癌性肝脏,TM4SF5、pYSTAT3、胶原 I 和层粘连蛋白 γ2 水平增强。TM4SF5 抑制剂 4'-(对甲苯磺酰胺基)-4-羟基查耳酮(TSAHC)消除了这些 TM4SF5 介导的作用。TM4SF5 依赖性肿瘤发生涉及自然杀伤(NK)细胞耗竭样表型,包括 NK 细胞数量或功能减少,用 TSAHC 治疗可阻断这些表型。癌细胞中的 TM4SF5 表达下调了 NK 细胞细胞毒性的刺激配体和受体,包括 SLAMF6、SLAMF7、MICA/B 等。TM4SF5 抑制或抑制降低了 STAT3 信号活性,并恢复了受体水平和 NK 细胞监视,导致纤维化和癌性表型减少,生存率延长。总之,这些发现表明,TM4SF5 介导的细胞外基质调节 STAT3 活性参与了肝病向 HCC 的进展,并且 TM4SF5 似乎在肝癌发生过程中抑制 NK 细胞。