Qiu Jianfa, Hu Feifei, Shao Tingting, Guo Yuqiang, Dai Zongmao, Nie Huanhuan, Olasunkanmi Oluwatayo Israel, Qi Yue, Chen Yang, Lin Lexun, Zhao Wenran, Zhong Zhaohua, Wang Yan
Department of Microbiology, Harbin Medical University, Harbin, China.
Department of Obstetrics, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
Front Oncol. 2021 Sep 27;11:633794. doi: 10.3389/fonc.2021.633794. eCollection 2021.
Human papillomavirus (HPV) is a double-stranded DNA (dsDNA) virus, and its high-risk subtypes increase cancer risks. However, the mechanism of HPV infection and pathogenesis still remain unclear. Therefore, understanding the molecular mechanisms and the pathogenesis of HPV are crucial in the prevention of HPV-related cancers. In this study, we analyzed cervix squamous cell carcinoma (CESC) and head and neck carcinoma (HNSC) combined data to investigate various HPV-induced cancer common features. We showed that epidermal growth factor receptor (EGFR) was downregulated in HPV-positive (HPV+) cancer, and that HPV+ cancer patients exhibited better prognosis than HPV-negative (HPV-) cancer patients. Our study also showed that TP53 mutation rate is lower in HPV+ cancer than in HPV- cancer and that TP53 can be modulated by HPV E7 protein. However, there was no significant difference in the expression of wildtype TP53 in both groups. Subsequently, we constructed HPV-human interaction network and found that EGFR is a critical factor. From the network, we also noticed that EGFR is regulated by HPV E7 protein and hsa-miR-944. Moreover, while phosphorylated EGFR is associated with a worse prognosis, EGFR total express level is not significantly correlated with prognosis. This indicates that EGFR activation will induce a worse outcome in HPV+ cancer patients. Further enrichment analysis showed that EGFR downstream pathway and cancer relative pathway are diversely activated in HPV+ cancer and HPV- cancer. In summary, HPV E7 protein downregulates EGFR that downregulates phosphorylated EGFR and inhibit EGFR-related pathways which in turn and consequently induce better prognosis.
人乳头瘤病毒（HPV）是一种双链DNA（dsDNA）病毒，其高危亚型会增加患癌风险。然而，HPV感染和发病机制仍不清楚。因此，了解HPV的分子机制和发病机制对于预防HPV相关癌症至关重要。在本研究中，我们分析了宫颈鳞状细胞癌（CESC）和头颈癌（HNSC）的联合数据，以研究各种HPV诱导的癌症的共同特征。我们发现，表皮生长因子受体（EGFR）在HPV阳性（HPV+）癌症中下调，并且HPV+癌症患者的预后比HPV阴性（HPV-）癌症患者更好。我们的研究还表明，HPV+癌症中的TP53突变率低于HPV-癌症，并且TP53可被HPV E7蛋白调节。然而，两组中野生型TP53的表达没有显著差异。随后，我们构建了HPV-人类相互作用网络，发现EGFR是一个关键因素。从该网络中，我们还注意到EGFR受HPV E7蛋白和hsa-miR-944调节。此外，虽然磷酸化EGFR与较差的预后相关，但EGFR总表达水平与预后没有显著相关性。这表明EGFR激活将导致HPV+癌症患者出现更差的结果。进一步的富集分析表明，EGFR下游通路和癌症相关通路在HPV+癌症和HPV-癌症中被不同程度地激活。总之，HPV E7蛋白下调EGFR，进而下调磷酸化EGFR并抑制EGFR相关通路，从而导致更好的预后。
