Muscle-invasive bladder cancer (MIBC) is associated with low survival and high recurrence rates even in cases in which patients receive systemic treatments, such as surgery and chemotherapy. Here, we found that a naturally existing alphavirus, namely, M1, selectively kills bladder cancer cells but not normal cells, findings supported by our observations of changes in viral replication and MIBC and patient-derived MIBC cell apoptosis. Transcriptome analysis revealed that interferon-stimulated genes (ISGs) are expressed at low levels in sensitive bladder cancer cells and high levels in resistant cells. Knocking down ZC3HAV1 (ZAP), an antiviral factor in ISGs, restores M1 virus reactivity in resistant cells, and overexpressing ZAP partially reverses M1 virus-induced decreases in cell viability in sensitive cells. In orthotopic MIBC mice, tail vein injections of M1 significant inhibit tumor growth and prolong survival period, antitumor effects of M1 are stronger than those of the first-line chemotherapy agent cisplatin (CDDP). Treated tumors display enhanced cleaved-caspase-3 signals, which are representative of cell apoptosis, and decreased Ki-67 signals, which are representative of cell proliferation. Moreover, tissue microarray (TMA) analyses of clinical tumor specimens revealed that up to 45.6% of cases of MIBC presented with low ZAP expression, a finding that is prevalent in advanced MIBC. Our results indicate that the oncolytic virus M1 is a novel agent capable of functioning as a precise and effective therapy for MIBC.
Cell death & disease. 2018 Feb 15*** epublish ***
Cheng Hu, Ying Liu, Yuan Lin, Jian-Kai Liang, Wen-Wen Zhong, Ke Li, Wen-Tao Huang, De-Juan Wang, Guang-Mei Yan, Wen-Bo Zhu, Jian-Guang Qiu, Xin Gao
Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China., Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China., Department of Pharmacology, Sun Yat-sen University, Guangzhou, China., Department of Urology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China., Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. ., Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. .