Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
Front Cell Infect Microbiol. 2024 Oct 22;14:1443868. doi: 10.3389/fcimb.2024.1443868. eCollection 2024.
Persistent infection with high-risk human papillomavirus (HR-HPV) is the main cause of cervical cancer. These chronic infections are characterized by high expression of the HPV E6 and E7 oncogenes and the absence of the L1 and L2 capsid proteins. The regulation of HPV gene expression plays a crucial role in both the viral life cycle and rare oncogenic events. Alternative splicing of HPV mRNA is a key mechanism in post-transcriptional regulation. Through alternative splicing, HPV mRNA is diversified into various splice isoforms with distinct coding potentials, encoding multiple proteins and influencing the expression of HPV genes. The spliced mRNAs derived from a donor splicing site within the E6 ORF and one of the different acceptor sites located in the early mRNA contain E6 truncated mRNAs, named E6*. E6* is one of the extensively studied splicing isoforms. However, the role of E6* proteins in cancer progression remains controversial. Here, we reviewed and compared the alternative splicing events occurring in the genomes of HR-HPV and LR-HPV. Recently, new HPV alternative splicing regulatory proteins have been continuously discovered, and we have updated the regulation of HPV alternative splicing. In addition, we summarized the functions of known splice isoforms from three aspects: anti-tumorigenic, tumorigenic, and other cancer-related functions, including not only E6*, but also E6^E7, E8^E2, and so on. Comprehending their contributions to cancer development enhances insights into the carcinogenic mechanisms of HPV and explores the potential utility of alternative splicing in the diagnosis and treatment of cervical cancer.
持续性感染高危型人乳头瘤病毒（HPV）是宫颈癌的主要病因。这些慢性感染的特征是 HPV E6 和 E7 癌基因的高表达，以及 L1 和 L2 衣壳蛋白的缺失。HPV 基因表达的调控在病毒生命周期和罕见致癌事件中都起着至关重要的作用。HPV mRNA 的可变剪接是转录后调控的关键机制。通过可变剪接，HPV mRNA 多样化为具有不同编码潜力的各种剪接异构体，编码多种蛋白质，并影响 HPV 基因的表达。源自 E6 ORF 内供体位点和早期 mRNA 中不同受体位点之一的剪接 mRNA 包含 E6 截断 mRNA，称为 E6*。E6是研究最多的剪接异构体之一。然而，E6蛋白在癌症进展中的作用仍存在争议。在这里，我们综述并比较了 HR-HPV 和 LR-HPV 基因组中发生的可变剪接事件。最近，不断发现新的 HPV 可变剪接调节蛋白，我们更新了 HPV 可变剪接的调控。此外，我们从三个方面总结了已知剪接异构体的功能：抗肿瘤、致瘤和其他与癌症相关的功能，包括不仅是 E6*，还有 E6^E7、E8^E2 等。理解它们对癌症发展的贡献增强了对 HPV 致癌机制的认识，并探讨了可变剪接在宫颈癌诊断和治疗中的潜在应用。
