Tumor-suppressive Function of Protein-tyrosine Phosphatase Non-receptor Type 23 in Testicular Germ Cell Tumors Is Lost upon Overexpression of miR142–3p microRNA

• Published in: The Journal of biological chemistry 2013-08, Vol.288 (33), p.23990-23999
• Main Authors: Tanaka, Kiyoko, Kondo, Keiichi, Kitajima, Kenji, Muraoka, Masatoshi, Nozawa, Akinori, Hara, Takahiko
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Animals; Base Sequence; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; MicroRNA; MicroRNAs - metabolism; Molecular Bases of Disease; Molecular Sequence Data; Neoplasms, Germ Cell and Embryonal - enzymology; Neoplasms, Germ Cell and Embryonal - genetics; Neoplasms, Germ Cell and Embryonal - pathology; Protein Tyrosine Phosphatases, Non-Receptor - metabolism; Testicular Germ Cell Tumor; Testicular Neoplasms - enzymology; Testicular Neoplasms - genetics; Testicular Neoplasms - pathology; Testis; Testis - enzymology; Testis - pathology; Tumor; Tumor Cell Biology; Tumor Suppressor Gene; Tumor Suppressor Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.478891

Protein-tyrosine phosphatase non-receptor type 23 (PTPN23) is a candidate tumor suppressor involved in the tumorigenesis of various organs. However, its physiological role(s) and detailed expression profile(s) have not yet been elucidated. We investigated the function and regulation of PTPN23 in the formation of testicular germ cell tumors (TGCTs). Expression of PTPN23 in human TGCT cell lines was significantly lower than that in spermatogonial stem cells in mice. Overexpression of PTPN23 in NEC8, a human TGCT cell line, suppressed soft agar colony formation in vitro and tumor formation in nude mice in vivo. These data indicate that PTPN23 functions as a tumor suppressor in TGCTs. Multiple computational algorithms predicted that the 3′ UTR of human PTPN23 is a target for miR-142-3p. A luciferase reporter assay confirmed that miR-142-3p bound directly to the 3′ UTR of PTPN23. Introduction of pre-miR-142 in the PTPN23 transfectant of NEC8 led to suppressed expression of PTPN23 and increased soft agar colony formation. Quantitative RT-PCR data revealed a significantly higher expression of miR-142-3p in human seminomas compared with normal testes. No difference in mRNA expression between seminoma and non-seminoma samples was detected by in situ hybridization. Both quantitative RT-PCR and immunohistochemical analyses revealed that PTPN23 expression was significantly lower in TGCTs than in normal testicular tissues. Finally, a lack of PTPN23 protein expression in human TGCTs correlated with a relatively higher miR-142-3p expression. These data suggest that PTPN23 is a tumor suppressor and that repression of PTPN23 expression by miR-142-3p plays an important role in the pathogenesis of TGCTs. Background: The PTPN23 gene is a candidate tumor suppressor involved in the tumorigenesis of various organs. Results: Expression of PTPN23 in testicular germ cell tumor cells is negatively regulated by miR-142-3p. Conclusion: A lack of PTPN23 protein expression in human TGCTs is inversely correlated with miR-142-3p expression. Significance: Loss of PTPN23 expression mediated by miR-142–3p may be a key event in the pathogenesis of TGCTs.