Biobank, Taizhou People's Hospital, Taizhou City, Jiangsu Province, P.R. China.
Eur Rev Med Pharmacol Sci. 2020 Feb;24(4):1829-1840. doi: 10.26355/eurrev_202002_20361.
Transmembrane-4-L- Six-Family-1 (TM4SF1) has been found involved in the development and progression of tumor. This study aims to investigate the effect of TM4SF1 on the proliferation, migration, and invasion of non-small cell lung cancer (NSCLC) and reveal its underlying mechanisms.
qRT-PCR, immunohistochemical analysis, and Western blot were used to evaluate the expression of TM4SF1 in human NSCLC tissues and cells. Cell proliferation was measured by CCK-8 and colony formation assay. Cell apoptosis was evaluated by flow cytometry assay. Cell migration and invasion were detected by wound healing and transwell assays. Co-immunoprecipitation (Co-IP) assay was used to examine the interactions between proteins. Expression levels of related proteins were determined by Western blot. For in vivo experiment, xenograft tumor models were used.
TM4SF1 was upregulated in NSCLC tissues and cell lines and closely correlated to survival time, tumor size, lymph node metastasis, distant metastasis, and clinical stage. Gain-of function and loss-of function experiments demonstrated the oncogenic effect of TM4SF1 on NSCLC cell proliferation, apoptosis, migration, and invasion. Notably, mechanism studies showed that TM4SF1 regulated the interaction between YAP and TEAD and the level of downstream target genes. Besides, sh-YAP or Peptide 17 treatment (YAP-TEAD protein-protein interaction inhibitor) reversed the effect of TM4SF1 on NSCLC cells. The in vivo research suggested that the knockdown of TM4SF1 inhibited the growth of xenograft tumor of NSCLC.
This is the first evidence demonstrating that TM4SF1 could promote proliferation, migration, and invasion in NSCLC, at least partially through a potential YAP-TEAD signaling pathway-dependent mechanism. This study might provide a potential therapeutic target for the treatment of NSCLC.
跨膜 4 超家族成员 1（TM4SF1）已被发现参与肿瘤的发生和发展。本研究旨在探讨 TM4SF1 对非小细胞肺癌（NSCLC）增殖、迁移和侵袭的影响，并揭示其潜在机制。
采用 qRT-PCR、免疫组织化学分析和 Western blot 检测 TM4SF1 在人 NSCLC 组织和细胞中的表达。CCK-8 和集落形成实验检测细胞增殖。流式细胞术检测细胞凋亡。划痕愈合和 Transwell 检测细胞迁移和侵袭。采用免疫共沉淀（Co-IP）实验检测蛋白相互作用。Western blot 检测相关蛋白表达水平。进行体内实验时，采用异种移植肿瘤模型。
TM4SF1 在 NSCLC 组织和细胞系中上调，与生存时间、肿瘤大小、淋巴结转移、远处转移和临床分期密切相关。功能获得和功能丧失实验表明，TM4SF1 对 NSCLC 细胞增殖、凋亡、迁移和侵袭具有致癌作用。值得注意的是，机制研究表明 TM4SF1 调节 YAP 和 TEAD 之间的相互作用以及下游靶基因的水平。此外，sh-YAP 或 Peptide 17 处理（YAP-TEAD 蛋白-蛋白相互作用抑制剂）逆转了 TM4SF1 对 NSCLC 细胞的作用。体内研究表明，TM4SF1 的敲低抑制了 NSCLC 异种移植瘤的生长。
这是首次证明 TM4SF1 可促进 NSCLC 增殖、迁移和侵袭的证据，至少部分通过潜在的 YAP-TEAD 信号通路依赖性机制。本研究可能为 NSCLC 的治疗提供一个潜在的治疗靶点。
