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

Huang, Kang-Bo1,2; Guo, Sheng-Jie1,2; Li, Yong-Hong1,2; Zhang, Xin-Ke1,3; Chen, Dong1,2; Spiess, Philippe E.4; Li, Zai-Shang5; Deng, Chuang-Zhong1,6; Chen, Jie-Ping1,7; Zhou, Qiang-Hua8; Hu, Zheng9; Ma, Xin10; Jin, Jie-Tian1,3; Cao, Yun1,3; Luo, Jun-Hang11; Wang, Xiao-Bin12; Zhou, Fang-Jian1,2; Liu, Ran-Yi1; Han, Hui1,2

2021-12-01

10.3390/cancers13236104

CANCERS   影响因子和分区

2072-6694

Simple Summary Penile squamous cell carcinoma (PSCC) has been regarded as an HPV-related cancer for a long time. However, the integration pattern and carcinogenic pathways of HPV in PSCC remain unclear. The results of this study provide insights into the HPV-related carcinogenic mechanism in PSCC, which may be less prone to involvement in the traditional E6/E7 carcinogenic process, and are characterized by effects on the host genome, which result in the inactivation of tumor suppressors (CADM2, etc.) and the activation of oncogenes (KLF5, etc.), thus activating oncogenic signaling pathways (MAPK, JAK/STAT, etc.). This study could enhance our understanding of HPV integration and pave the way for subsequent HPV studies in PSCC. 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.

penile squamous cell carcinoma human papillomavirus E2 MAPK signaling pathway CADM2

SCI

英语

其他

Oncology

Oncology

WOS:000741527100001

MDPI

Web of Science

1.Sun Yat Sen Univ, State Key Lab Oncol South China, Collaborat Innovat Ctr Canc Med, Ctr Canc, Guangzhou 510060, Peoples R China
2.Sun Yat Sen Univ, Dept Urol, Ctr Canc, Guangzhou 510060, Peoples R China
3.Sun Yat Sen Univ, Dept Pathol, Ctr Canc, Guangzhou 510060, Peoples R China
4.H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA
5.Southern Univ Sci & Technol, Dept Urol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Shenzhen 518020, Peoples R China
6.Sun Yat Sen Univ, Dept Orthoped, Ctr Canc, Guangzhou 510060, Peoples R China
7.Sun Yat Sen Univ, Dept Gynecol, Ctr Canc, Guangzhou 510060, Peoples R China
8.Sun Yat Sen Mem Hosp, Dept Urol, Guangzhou 510120, Peoples R China
9.Sun Yat Sen Univ, Dept Obstet & Gynecol, Precis Med Inst, Affiliated Hosp 1, Guangzhou 510080, Peoples R China
10.Gen Hosp Peoples Liberat Army, Dept Urol, Beijing 100853, Peoples R China
11.Sun Yat Sen Univ, Dept Urol, Affiliated Hosp 1, Guangzhou 510080, Peoples R China
12.MyGenostics Inc, Beijing 101318, Peoples R China

Huang, Kang-Bo,Guo, Sheng-Jie,Li, Yong-Hong,et al. Genome-Wide Profiling Reveals HPV Integration Pattern and Activated Carcinogenic Pathways in Penile Squamous Cell Carcinoma[J]. CANCERS,2021,13(23).

Huang, Kang-Bo.,Guo, Sheng-Jie.,Li, Yong-Hong.,Zhang, Xin-Ke.,Chen, Dong.,...&Han, Hui.(2021).Genome-Wide Profiling Reveals HPV Integration Pattern and Activated Carcinogenic Pathways in Penile Squamous Cell Carcinoma.CANCERS,13(23).

Huang, Kang-Bo,et al."Genome-Wide Profiling Reveals HPV Integration Pattern and Activated Carcinogenic Pathways in Penile Squamous Cell Carcinoma".CANCERS 13.23(2021).