癌基因介导的 THG-1/TSC22D4 磷酸化促进鳞状细胞癌肿瘤发生,Cancer Science

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癌基因介导的 THG-1/TSC22D4 磷酸化促进鳞状细胞癌肿瘤发生
Cancer Science ( IF 4.5 ) Pub Date : 2023-08-22 , DOI: 10.1111/cas.15934
Nohara Goto _{1,

2} , Hiroyuki Suzuki _{1,

3} , Ling Zheng ₁ , Yasuhito Okano ₁ , Yukari Okita ₁ , Yukihide Watanabe ₁ , Yukinari Kato ₃ , Mitsuyasu Kato ₁

Affiliation

癌细胞具有高增殖和侵袭潜力，并表现出抵抗压力、代谢紊乱和治疗努力的能力。这些特性主要是通过基因改变（包括驱动基因突变）获得的。然而，详细的分子机制尚未完全阐明。在这里，我们提供了一种通过转化生长因子-β1 刺激的克隆 22 (TSC-22) 家族蛋白 THG-1（也称为 TSC22D4）连接致癌信号和致瘤特性的新机制。THG-1 位于正常鳞状上皮的基底层，并在鳞状细胞癌 (SCC) 中过度表达。THG-1 敲低可抑制 SCC 细胞增殖、侵袭性和异种移植肿瘤形成。相反，THG-1过表达促进EGF诱导的增殖和复层上皮形成。此外，THG-1被受体酪氨酸激酶（RTK）-RAS-ERK通路磷酸化，促进癌基因介导的肿瘤发生。此外，THG-1 参与 CD44 变体的选择性剪接，CD44 变体是 RTK 途径下侵袭性、干性和氧化应激抗性的调节因子。这些发现强调了 THG-1 作为 SCC 肿瘤发生的新型效应物的关键作用，并且通过我们建立的特异性抗体检测 THG-1 磷酸化可能有助于癌症诊断和治疗。

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Promotion of squamous cell carcinoma tumorigenesis by oncogene-mediated THG-1/TSC22D4 phosphorylation

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.

更新日期：2023-08-22

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