癌细胞具有高增殖和浸润能力，并对压力、代谢紊乱和治疗努力表现出耐受力。这些特性主要通过包括驱动基因突变在内的遗传改变获得。然而，这些详细的分子机制尚未完全阐明。在这里，我们提供了一个新的机制，将致癌信号和肿瘤特性连接起来，这个机制是由转化生长因子-β1刺激的克隆22 (TSC-22) 家族蛋白THG-1 (也被称为TSC22D4) 实现的。THG-1定位在正常鳞状上皮的基底层，并在鳞状细胞癌中过表达。THG-1的沉默抑制了鳞状细胞癌增殖、浸润和异种移植瘤形成。相反，THG-1的过表达促进了EGF诱导的增殖和分层上皮形成。此外，THG-1被受体酪氨酸激酶(RTK)-RAS-ERK通路磷酸化，从而促进了致癌基因介导的肿瘤发生。此外，THG-1参与了CD44变异体的剪接，CD44是RTK通路下的浸润、干性和氧化应激抵抗的调节因子。这些发现凸显了THG-1在鳞状细胞癌肿瘤发生中的重要作用，而通过我们建立的特异性抗体检测THG-1的磷酸化可能有助于癌症的诊断和治疗。© 2023 The Authors. 由John Wiley & Sons Australia, Ltd代表日本癌症协会出版的《Cancer Science》发布。

Carcinoma cells possess high proliferative and invasive potentials and exhibit a resilience against stresses, metabolic disorder, and therapeutic efforts. These properties are mainly acquired by genetic alterations including driver gene mutations. However, the detailed molecular mechanisms have not been fully elucidated. Here, we provide a novel mechanism connecting oncogenic signaling and the tumorigenic properties by a transforming growth factor-β1-stimulated clone 22 (TSC-22) family protein, THG-1 (also called as TSC22D4). THG-1 is localized at the basal layer of normal squamous epithelium and overexpressed in squamous cell carcinomas (SCCs). THG-1 knockdown suppressed SCC cell proliferation, invasiveness, and xenograft tumor formation. In contrast, THG-1 overexpression promoted the EGF-induced proliferation and stratified epithelium formation. Furthermore, THG-1 is phosphorylated by the receptor tyrosine kinase (RTK)-RAS-ERK pathway, which promoted the oncogene-mediated tumorigenesis. Moreover, THG-1 involves in the alternative splicing of CD44 variants, a regulator of invasiveness, stemness, and oxidative stress resistance under the RTK pathway. These findings highlight the pivotal roles of THG-1 as a novel effector of SCC tumorigenesis, and the detection of THG-1 phosphorylation by our established specific antibody could contribute to cancer diagnosis and therapy.© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.