Genome-Wide Profiling Reveals HPV Integration Pattern and Activated Carcinogenic Pathways in Penile Squamous Cell Carcinoma

Cancers

Zheng Hu¹  Zai-Shang Li²  Qiang-Hua Zhou³  Jun-Hang Luo⁴  Xin Ma⁵  Philippe E. Spiess⁶  Xiao-Bin Wang⁷  Fang-Jian Zhou⁸  Kang-Bo Huang⁸  Jie-Ping Chen⁸  Sheng-Jie Guo⁸  Dong Chen⁸  Jie-Tian Jin⁸  Yun Cao⁸  Hui Han⁸  Ran-Yi Liu⁸  Xin-Ke Zhang⁸  Chuang-Zhong Deng⁸  Yong-Hong Li⁸ 

[1] Department of Obstetrics and Gynecology, Precision Medicine Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China;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 Urology, 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;H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;MyGenostics Inc., Beijing 101318, China;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China;

关键词: penile squamous cell carcinoma;    human papillomavirus;    E2;    MAPK signaling pathway;    CADM2;   

DOI  :  10.3390/cancers13236104

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown