Key Laboratory of Smart Farming for Agricultural Animals and Hubei Key Laboratory of Agricultural Bioinformatics, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan, Hubei, China.
Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
J Med Virol. 2023 May;95(5):e28789. doi: 10.1002/jmv.28789.
Integration of human papilloma virus (HPV) DNA into the human genome may progressively contribute to cervical carcinogenesis. To explore how HPV integration affects gene expression by altering DNA methylation during carcinogenesis, we analyzed a multiomics dataset for cervical cancer. We obtained multiomics data by HPV-capture sequencing, RNA sequencing, and Whole Genome Bisulfite Sequencing from 50 patients with cervical cancer. We detected 985 and 485 HPV-integration sites in matched tumor and adjacent paratumor tissues. Of these, LINC00486 (n = 19), LINC02425 (n = 11), LLPH (n = 11), PROS1 (n = 5), KLF5 (n = 4), LINC00392 (n = 3), MIR205HG (n = 3) and NRG1 (n = 3) were identified as high-frequency HPV-integrated genes, including five novel recurrent genes. Patients at clinical stage II had the highest number of HPV integrations. E6 and E7 genes of HPV16 but not HPV18 showed significantly fewer breakpoints than random distribution. HPV integrations occurring in exons were associated with altered gene expression in tumor tissues but not in paratumor tissues. A list of HPV-integrated genes regulated at transcriptomic or epigenetic level was reported. We also carefully checked the candidate genes with regulation pattern correlated in both levels. HPV fragments integrated at MIR205HG mainly came from the L1 gene of HPV16. RNA expression of PROS1 was downregulated when HPV integrated in its upstream region. RNA expression of MIR205HG was elevated when HPV integrated into its enhancer. The promoter methylation levels of PROS1 and MIR205HG were all negatively correlated with their gene expressions. Further experimental validations proved that upregulation of MIR205HG could promote the proliferative and migrative abilities of cervical cancer cells. Our data provides a new atlas for epigenetic and transcriptomic regulations regarding HPV integrations in cervical cancer genome. We demonstrate that HPV integration may affect gene expression by altering methylation levels of MIR205HG and PROS1. Our study provides novel biological and clinical insights into HPV-induced cervical cancer.
人乳头瘤病毒（HPV）DNA 整合到人类基因组中可能会逐渐促进宫颈癌的发生。为了探索 HPV 整合如何通过改变致癌过程中的 DNA 甲基化来影响基因表达，我们分析了宫颈癌的多组学数据集。我们从 50 名宫颈癌患者的肿瘤和相邻癌旁组织中获得了 HPV 捕获测序、RNA 测序和全基因组亚硫酸氢盐测序的多组学数据。我们在匹配的肿瘤和癌旁组织中检测到了 985 个和 485 个 HPV 整合位点。其中，LINC00486(n=19)、LINC02425(n=11)、LLPH(n=11)、PROS1(n=5)、KLF5(n=4)、LINC00392(n=3)、MIR205HG(n=3)和 NRG1(n=3)被鉴定为高频 HPV 整合基因，包括五个新的复发性基因。临床分期为 II 期的患者 HPV 整合数量最多。HPV16 的 E6 和 E7 基因而不是 HPV18 的 E6 和 E7 基因的断点明显少于随机分布。发生在外显子中的 HPV 整合与肿瘤组织中基因表达的改变有关，但与癌旁组织无关。报告了一组在转录组或表观遗传水平受到调控的 HPV 整合基因。我们还仔细检查了在这两个水平上的调控模式相关的候选基因。整合到 MIR205HG 的 HPV 片段主要来自 HPV16 的 L1 基因。当 HPV 整合到 PROS1 的上游区域时，其 RNA 表达下调。当 HPV 整合到 MIR205HG 的增强子时，MIR205HG 的 RNA 表达升高。PROS1 和 MIR205HG 的启动子甲基化水平均与基因表达呈负相关。进一步的实验验证表明，MIR205HG 的上调可以促进宫颈癌细胞的增殖和迁移能力。我们的数据为宫颈癌基因组中 HPV 整合的表观遗传和转录组调控提供了一个新的图谱。我们证明 HPV 整合可能通过改变 MIR205HG 和 PROS1 的甲基化水平来影响基因表达。我们的研究为 HPV 诱导的宫颈癌提供了新的生物学和临床见解。
