Yang Min, Ma Yuejiang, Cao Zhu, Zhan Hong, Jin Ye, Huang Xiufeng, Yang Shizhou
Department of Ambulatory Surgery, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, 1# Xueshi Road, Shangcheng District, Hangzhou, 310006, Zhejiang, China.
Biochem Genet. 2025 Jun 10. doi: 10.1007/s10528-025-11144-w.
Cervical cancer (CC) is one of the most prevalent cancers among women globally. The primary cause of CC is persistent infection with high-risk types of human papillomavirus (HPV), particularly HPV16, whose E7 oncoprotein plays a pivotal role in carcinogenesis and the maintenance of stem cell-like characteristics. RTKN2 participates in the progression of various cancers. However, the precise functions of RTKN2 in regulating CC remain unclear. The effects of HPV16 E7 in CC cells were evaluated using MTT, western blotting, Transwell, and sphere formation assays. Transcriptome sequencing and bioinformatics analyses were used to identify the targets of HPV16 E7. The expression levels of the target (RTKN2) in clinical samples were assessed using immunohistochemistry (IHC). The function and mechanism of RTKN2 in CC cells were investigated by the knockdown and overexpression approaches, as well as dual-luciferase reporter assay. HPV16 E7 exhibited a positive correlation on the malignant phenotype and stemness of CC cells. RTKN2 was identified as a target of HPV16 E7, and a reduction in its expression levels was caused by knockdown of HPV16 E7. The high expression of RTKN2 was associated with a poor prognosis in CC. HPV16 E7 may regulate RTKN2 expression by modulating the binding activity of E2F1 to the RTKN2 promoter. Upregulated RTKN2 activates the NF-κB signaling pathway, enhances the stemness of CC cells, and ultimately promotes malignant progression.
宫颈癌（CC）是全球女性中最常见的癌症之一。CC的主要病因是高危型人乳头瘤病毒（HPV）的持续感染，尤其是HPV16，其E7癌蛋白在致癌作用和维持干细胞样特征中起关键作用。RTKN2参与多种癌症的进展。然而，RTKN2在调节CC中的精确功能仍不清楚。使用MTT、蛋白质免疫印迹、Transwell和球体形成试验评估HPV16 E7对CC细胞的影响。利用转录组测序和生物信息学分析来鉴定HPV16 E7的靶标。使用免疫组织化学（IHC）评估临床样本中靶标（RTKN2）的表达水平。通过敲低和过表达方法以及双荧光素酶报告基因试验研究RTKN2在CC细胞中的功能和机制。HPV16 E7与CC细胞的恶性表型和干性呈正相关。RTKN2被鉴定为HPV16 E7的靶标，敲低HPV16 E7会导致其表达水平降低。RTKN2的高表达与CC患者的不良预后相关。HPV16 E7可能通过调节E2F1与RTKN2启动子的结合活性来调节RTKN2的表达。上调的RTKN2激活NF-κB信号通路，增强CC细胞的干性，并最终促进恶性进展。
