Human papillomavirus (HPV) is a significant etiologic driver of penile squamous cell carcinoma (PSCC). The integration pattern of HPV and its carcinogenic mechanism in PSCC remain largely unclear. We retrospectively reviewed 108 PSCC cases who received surgery between 2008 and 2017. Using high-throughput viral integration detection, we identified 35 HPV-integrated PSCCs. Unlike cervical cancer, the HPV E2 oncogene was not prone to involvement in integration. Eleven of the 35 (31.4%) HPV-integrated PSCCs harbored intact HPV E2; these tumors had lower HPV E6 and E7 expression and higher expression of p53 and pRb proteins than those with disrupted E2 did (p < 0.001 and p = 0.024). Integration breakpoints are preferentially distributed in or near host genes, including previously reported hotspots (KLF5, etc.) and newly identified hotspots (CADM2, etc.), which are mainly involved in oncogenic signaling pathways (MAPK, JAK/STAT, etc.). Regarding the phosphorylation levels of JNK, p38 was higher in HPV-positive tumors with MAPK-associated integration than those in HPV-positive tumors with other integration and those in HPV-negative tumors. In vitro, KLF5 knockdown inhibited proliferation and invasion of PSCC cells, while silencing CADM2 promoted migration and invasion. In conclusion, this study enhances our understanding of HPV-induced carcinogenesis in PSCC, which may not only rely on the E6/E7 oncogenes, but mat also affect the expression of critical genes and thus activate oncogenic pathways.
Cancers. 2021 Dec 03*** epublish ***
Kang-Bo Huang, Sheng-Jie Guo, Yong-Hong Li, Xin-Ke Zhang, Dong Chen, Philippe E Spiess, Zai-Shang Li, Chuang-Zhong Deng, Jie-Ping Chen, Qiang-Hua Zhou, Zheng Hu, Xin Ma, Jie-Tian Jin, Yun Cao, Jun-Hang Luo, Xiao-Bin Wang, Fang-Jian Zhou, Ran-Yi Liu, Hui Han
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Department of Urology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China., Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou 510120, China., Department of Obstetrics and Gynecology, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China., Department of Urology, The General Hospital of the People's Liberation Army, Beijing 100853, China., Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China., MyGenostics Inc., Beijing 101318, China.