Abstract
Simple SummaryPenile 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.
Highlights
Penile squamous cell carcinoma (PSCC) is a rare malignancy worldwide, but its incidence is much higher in developing areas such as Africa, South America, and Southeast Asia
2252 Human papillomavirus (HPV) integration breakpoints were identified in 35 penile squamous cell carcinoma (PSCC) specimens (Supplementary Tables S8 and S9)
As HPV integration could induce carcinogenesis by activating oncogenes or inactivating tumor suppressors in the human genome, to investigate which gene and signaling pathway play a key role in HPV-induced PSCC, we identified 2277 genes that were likely affected by HPV integration (Supplementary Table S10)
Summary
Penile squamous cell carcinoma (PSCC) is a rare malignancy worldwide, but its incidence is much higher in developing areas such as Africa, South America, and Southeast Asia. The HPV genome is detected as integrated rather than episomal in tumors [2]. The integration of the HPV genome into the host genome has an important role in HPV-induced carcinogenesis. According to studies of other HPV-related cancers, the most common carcinogenic process is E6/E7-induced carcinogenesis triggered by disruption of the HPV E2 oncogene: The disruption of E2 results in a loss of negative feedback control of the expression of the E6 and E7 viral oncoproteins that are involved in the inactivation of p53 and pRb proteins [3–5]. Besides traditional E6/E7-induced carcinogenesis, in some cases, HPV integration induces carcinogenesis through directly activating oncogenes or inactivating tumor suppressors in the human genome [6,7]. In other HPV-related cancers, thousands of HPV integration sites in the human genome have been identified, and many distribute near the known cancer driver genes [8,9]. The carcinogenic mechanism of HPV integration in PSCC remains largely unknown
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