Genome-Wide Profiling Reveals HPV Integration Pattern and Activated Carcinogenic Pathways in Penile Squamous Cell Carcinoma.
Genome-Wide Profiling Reveals HPV Integration Pattern and Activated Carcinogenic Pathways in Penile Squamous Cell Carcinoma.
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全基因组分析揭示阴茎鳞状细胞癌中的 HPV 整合模式和激活的致癌途径
DOI：
10.3390/cancers13236104
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发表时间：
2021-12-03
期刊：
影响因子：
5.2
通讯作者：
Han H
中科院分区：
文献类型：
--
作者：
Huang KB;Guo SJ;Li YH;Zhang XK;Chen D;Spiess PE;Li ZS;Deng CZ;Chen JP;Zhou QH;Hu Z;Ma X;Jin JT;Cao Y;Luo JH;Wang XB;Zhou FJ;Liu RY;Han H
阴茎鳞状细胞癌（PSCC）长期以来被认为是一种与hpv相关的癌症。然而，HPV在PSCC中的整合模式和致癌途径尚不清楚。本研究结果揭示了hpv在PSCC中的相关致癌机制，PSCC可能较少参与传统的E6/E7致癌过程，其特点是作用于宿主基因组，导致抑癌基因（CADM2等）失活，致癌基因（KLF5等）激活，从而激活致癌信号通路（MAPK、JAK/STAT等）。该研究可以增强我们对HPV整合的理解，并为后续HPV在PSCC中的研究铺平道路。人乳头瘤病毒（HPV）是阴茎鳞状细胞癌（PSCC）的重要病因驱动因素。HPV在PSCC中的整合模式及其致癌机制仍不清楚。我们回顾性分析了2008年至2017年间接受手术的108例PSCC病例。使用高通量病毒整合检测，我们鉴定了35个hpv整合的PSCCs。与宫颈癌不同，HPV E2癌基因不容易参与整合。35例HPV整合PSCCs中有11例（31.4%）携带完整的HPV E2；与E2被破坏的肿瘤相比，这些肿瘤的HPV E6和E7表达较低，p53和pRb表达较高（p < 0.001和p = 0.024）。整合断点优先分布在宿主基因内或附近，包括先前报道的热点（KLF5等）和新发现的热点（CADM2等），主要参与致癌信号通路（MAPK、JAK/STAT等）。JNK的磷酸化水平，在mapk相关整合的hpv阳性肿瘤中，p38高于其他整合的hpv阳性肿瘤和hpv阴性肿瘤。在体外，KLF5敲低抑制PSCC细胞的增殖和侵袭，而CADM2沉默促进PSCC细胞的迁移和侵袭。总之，本研究增强了我们对hpv诱导的PSCC癌变的认识，PSCC癌变可能不仅依赖于E6/E7癌基因，还可能影响关键基因的表达，从而激活致癌途径。
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.
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