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Tumor-promoting function and prognostic significance of the RNA-binding protein T-cell intracellular antigen-1 in esophageal squamous cell carcinoma

2016; Impact Journals LLC; Volume: 7; Issue: 13 Linguagem: Inglês

10.18632/oncotarget.7937

1949-2553

Junichi Hamada, Katsutoshi Shoda, Kiyoshi Masuda, Yuji Fujita, Takuya Naruto, Tomohiro Kohmoto, Yuko Miyakami, Miki Watanabe, Yasusei Kudo, Hitoshi Fujiwara, Daisuke Ichikawa, Eigo Otsuji, Issei Imoto,

RNA Research and Splicing

// Junichi Hamada 1, 2, * , Katsutoshi Shoda 1, 2, * , Kiyoshi Masuda 1, * , Yuji Fujita 1, 2 , Takuya Naruto 1 , Tomohiro Kohmoto 1, 3 , Yuko Miyakami 1, 3 , Miki Watanabe 1, 3 , Yasusei Kudo 4 , Hitoshi Fujiwara 2 , Daisuke Ichikawa 2 , Eigo Otsuji 2 , Issei Imoto 1 1 Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan 2 Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan 3 Student Lab, Tokushima University Faculty of Medicine, Tokushima, 770-8503, Japan 4 Department of Oral Molecular Pathology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan * These authors contributed equally to this work Correspondence to: Issei Imoto, e-mail: issehgen@tokushima-u.ac.jp Keywords: T-cell intracellular antigen-1, isoform, oncogene, RNA-binding protein, esophageal squamous cell carcinoma Received: October 01, 2015 Accepted: February 05, 2016 Published: March 06, 2016 ABSTRACT T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein involved in many regulatory aspects of mRNA metabolism. Here, we report previously unknown tumor-promoting activity of TIA1, which seems to be associated with its isoform-specific molecular distribution and regulation of a set of cancer-related transcripts, in esophageal squamous cell carcinoma (ESCC). Immunohistochemical overexpression of TIA1 ectopically localized in the cytoplasm of tumor cells was an independent prognosticator for worse overall survival in a cohort of 143 ESCC patients. Knockdown of TIA1 inhibited proliferation of ESCC cells. By exogenously introducing each of two major isoforms, TIA1a and TIA1b, only TIA1a, which was localized to both the nucleus and cytoplasm, promoted anchorage-dependent and anchorage-independent ESCC cell proliferation. Ribonucleoprotein immunoprecipitation, followed by microarray analysis or massive-parallel sequencing, identified a set of TIA1-binding mRNAs, including SKP2 and CCNA2 . TIA1 increased SKP2 and CCNA2 protein levels through the suppression of mRNA decay and translational induction, respectively. Our findings uncover a novel oncogenic function of TIA1 in esophageal tumorigenesis, and implicate its use as a marker for prognostic evaluation and as a therapeutic target in ESCC.