Affiliation:
1. Department of Experimental Pathology, Faculty of Medicine University of Tsukuba Tsukuba Japan
2. Ph.D. Program in Human Biology, School of Integrative and Global Majors University of Tsukuba Tsukuba Japan
3. Department of Antibody Drug Development Tohoku University Graduate School of Medicine Sendai Japan
Abstract
AbstractCarcinoma 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.
Funder
Japan Society for the Promotion of Science
Subject
Cancer Research,Oncology,General Medicine