人乳头瘤病毒 E7 癌蛋白通过转录因子 E2F1 促进宫颈癌细胞的增殖和迁移。

Human Papillomavirus E7 Oncoprotein Promotes Proliferation and Migration through the Transcription Factor E2F1 in Cervical Cancer Cells.

机构信息

Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Department of Gynecology and Obstetrics, China-Japan Friendship Hospital, Beijing, China.

出版信息

Anticancer Agents Med Chem. 2021;21(13):1689-1696. doi: 10.2174/1871520620666201106085227.

DOI:10.2174/1871520620666201106085227

PMID:33155930

Abstract

BACKGROUND

High-Risk Human Papillomavirus (HR-HPV) persistent infection is the main cause of cervical cancer and its precancerous lesions. A previous study showed that HPV16 and HPV58 infections were the most common infection types in the local region. Some studies also declared that HPV58 E7 variants increased the risk of cervical cancer among Asian populations.

OBJECTIVE

This study aimed to determine whether the HPV58 E7 T20I (C632T) variant promotes the malignant behavior of cervical cancer cells and the underlying mechanism of the HR-HPV E7 oncoprotein involved in the development of cervical cancer.

METHODS

CCK-8 and clone formation assays were used to detect cell proliferation ability. Transwell assays and cell wound healing assays were used to evaluate cell migration ability. Targeted knockdown of E2F1 expression using specific siRNA, RT-qPCR and Western blot were performed to assess gene expression changes. A chromatin immunoprecipitation assay was used to verify that E2F1 interacted with the TOP2A promoter region.

RESULTS

HPV58 E7 and HPV58 E7M oncoproteins increased the proliferation and migration ability of cervical cancer cells. However, the HPV58 E7 T20I variant did not promote malignant behaviors compared with wildtype HPV58 E7. HPV E7 and E7M oncoproteins increased the expression of TOP2A, BIRC5 and E2F1, and knockdown of HPV E7 decreased their expression. Low E2F1 expression reduced the expression of TOP2A and BIRC5 and inhibited the proliferation and migration ability of cervical cancer cells. E2F1 interacted with the TOP2A gene promoter region to promote its transcriptional expression.

CONCLUSION

The HPV58 E7 T20I variant did not promote malignant behaviors compared with wild-type HPV58 E7. The HR-HPV E7 oncoprotein enhanced the proliferation and migration of cervical cancer cells, which was considered to be due to the HPV E7 oncoprotein, increasing the expression of BIRC5 and TOP2A by upregulating the transcription factor E2F1.

摘要

背景

高危型人乳头瘤病毒（HR-HPV）持续感染是宫颈癌及其癌前病变的主要原因。先前的研究表明，HPV16 和 HPV58 感染是该地区最常见的感染类型。一些研究还宣称 HPV58 E7 变体增加了亚洲人群宫颈癌的风险。

目的

本研究旨在确定 HPV58 E7 T20I（C632T）变体是否促进宫颈癌细胞的恶性行为，以及 HR-HPV E7 癌蛋白在宫颈癌发展中的潜在机制。

方法

使用 CCK-8 和克隆形成实验检测细胞增殖能力。使用 Transwell 实验和细胞划痕愈合实验评估细胞迁移能力。使用特异性 siRNA、RT-qPCR 和 Western blot 靶向敲低 E2F1 表达，评估基因表达变化。使用染色质免疫沉淀实验验证 E2F1 是否与 TOP2A 启动子区域相互作用。

结果

HPV58 E7 和 HPV58 E7M 癌蛋白增加了宫颈癌细胞的增殖和迁移能力。然而，与野生型 HPV58 E7 相比，HPV58 E7 T20I 变体并没有促进恶性行为。HPV E7 和 E7M 癌蛋白增加了 TOP2A、BIRC5 和 E2F1 的表达，而 HPV E7 的敲低降低了它们的表达。低 E2F1 表达降低了 TOP2A 和 BIRC5 的表达，并抑制了宫颈癌细胞的增殖和迁移能力。E2F1 与 TOP2A 基因启动子区域相互作用，促进其转录表达。