Inactivation of REV7 enhances chemosensitivity and overcomes acquired chemoresistance in testicular germ cell tumors

• Published in: Cancer letters Vol. 489; pp. 100 - 110
• Main Authors: Sakurai, Yasutaka, Ichinoe, Masaaki, Yoshida, Kazuki, Nakazato, Yuka, Saito, Shoji, Satoh, Masashi, Nakada, Norihiro, Sanoyama, Itaru, Umezawa, Atsuko, Numata, Yoshiko, Shi-Xu, Jiang, Ichihara, Masatoshi, Takahashi, Masahide, Murakumo, Yoshiki
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01-10-2020; Elsevier Limited
• Subjects: Animals; Antibodies; Apoptosis; Cell cycle; Cell lines; Cell proliferation; Chemoresistance; Chemotherapy; Cisplatin; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA microarrays; DNA repair; Doxorubicin; Drug Resistance, Neoplasm - physiology; Esophageal cancer; Gene expression; Gene Expression Regulation, Neoplastic - physiology; Heterografts; Humans; Immunohistochemistry; Mad2 Proteins - metabolism; Male; Medical prognosis; Medical research; Mice; Mice, Inbred NOD; Mice, SCID; Mutagenesis; Neoplasms, Germ Cell and Embryonal - pathology; Ovarian cancer; Proteins; Testes; Testicular Neoplasms - pathology; Translesion synthesis; Tumors; United States > US; Japan; Chemotherapy; Translesion synthesis; DNA damage; Cisplatin; Apoptosis
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2020.06.001

REV7 is a multitasking protein involved in replication past DNA lesions, cell cycle regulation, and gene expression. REV7 is highly expressed in the adult testis and plays an essential role in primordial germ cell maintenance in mice. In this study, we analyzed whether REV7 can be a molecular target for the treatment of testicular germ cell tumors (TGCTs), in which acquired chemoresistance is a major cause of treatment failure. Strong expression of REV7 was detected in human TGCT tissues by immunohistochemistry. REV7 depletion in the TGCT cell lines suppressed cell proliferation and increased sensitivity to cisplatin and doxorubicin. cDNA microarray analysis revealed that REV7 depletion downregulated genes in the DNA repair gene set and upregulated genes in the apoptosis gene set. REV7 depletion-provoked chemosensitivity was associated with DNA double-strand break accumulation and apoptosis activation. In addition, inactivation of REV7 in cisplatin-resistant TGCT cells recovered chemosensitivity at almost equal levels as parental cells in vitro and in vivo. Our results indicate that inactivation of REV7 enhances chemosensitivity and overcomes chemoresistance in TGCT cells, suggesting REV7 as a potential therapeutic target in chemoresistant TGCTs.
•Chemoresistance is a main issue in management of testicular germ cell tumor (TGCT).•REV7 is highly expressed in human TGCT tissues.•REV7 inactivation facilitates chemosensitivity in TGCT cells.•REV7 inactivation overcomes acquired chemoresistance in TGCT in vitro and in vivo.•REV7 is a potential therapeutic target in chemoresistant TGCTs.