Testis-expressed gene 11 inhibits cisplatin-induced DNA damage and contributes to chemoresistance in testicular germ cell tumor.

Abstract

Testicular germ cell tumor (TGCT) is a rare cancer but the most common tumor among adolescent and young adult males. Patients with advanced TGCT often exhibit a worse prognosis due to the acquisition of therapeutic resistance. Cisplatin-based chemotherapy is a standard treatment for advanced TGCTs initially sensitive to cisplatin, as exemplified by embryonal carcinoma. The acquisition of cisplatin resistance, however, could be a fatal obstacle for TGCT management. To identify cisplatin resistance-related genes, we performed transcriptome analysis for cisplatin-resistant TGCT cells compared to parental cells. In two types of cisplatin-resistant TGCT cell models that we established from patient-derived TGCT cells, and from the NEC8 cell line, we found that mRNA levels of the high-mobility-group nucleosome-binding gene HMGN5 and meiosis-related gene TEX11 were remarkably upregulated compared to those in the corresponding parental cells. We showed that either HMGN5 or TEX11 knockdown substantially reduced the viability of cisplatin-resistant TGCT cells in the presence of cisplatin. Notably, TEX11 silencing in cisplatin-resistant TGCT cells increased the level of cleaved PARP1 protein, and the percentage of double-strand break marker γH2AX-positive cells. We further demonstrated the therapeutic efficiency of TEX11-specific siRNA on in vivo xenograft models derived from cisplatin-resistant patient-derived TGCT cells. Taken together, the present study provides a potential insight into a mechanism of cisplatin resistance via TEX11-dependent pathways that inhibit apoptosis and DNA damage. We expect that our findings can be applied to the improvement of cisplatin-based chemotherapy for TGCT, particularly for TEX11-overexpressing tumor.

• Authors: Sachi Kitayama, Kazuhiro Ikeda, Wataru Sato, Hideki Takeshita, Satoru Kawakami, Satoshi Inoue, Kuniko Horie
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 18423 (11 01 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 36319719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Cisplatin
• HMGN Proteins
• HMGN5 protein, human
• Trans-Activators
• TEX11 protein, human

Topics

• Adolescent
• Humans
• Male
• Cell Line, Tumor
• Cisplatin (pharmacology)
• DNA Damage
• Drug Resistance, Neoplasm
• HMGN Proteins
• Neoplasms, Germ Cell and Embryonal
• Testicular Neoplasms (genetics)
• Testis (metabolism)
• Trans-Activators (genetics)