机构：[1]Department of Dermatovenereology, The Seventh Affiliated Hospital, Sun Yat‐sen University, Shenzhen, Guangdong, P. R. China深圳市康宁医院深圳医学信息中心[2]Department of Pathology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, P. R. China[3]Department of Dermatovenereology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P. R. China[4]Research Center, The Seventh Affiliated Hospital, Sun Yat‐sen University, Shenzhen, Guangdong, P. R. China[5]Department of Gynaecology and Obstetrics, The Seventh Affiliated Hospital, Sun Yat‐sen University, Shenzhen, Guangdong, P. R. China深圳市康宁医院深圳医学信息中心[6]Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, P. R. China
The mechanism of m6A modification in HPV-related cervical cancer remains unclear. This study explored the role of methyltransferase components in HPV-related cervical cancer and the mechanism. The levels of methyltransferase components and autophagy, ubiquitylation of RBM15 protein and the co-localization of lysosomal markers LAMP2A and RBM15 were measured. CCK-8 assay, flow cytometry, clone formation experiment and immunofluorescence assay were conducted to measure cell proliferation. The mouse tumor model was developed to study the cell growth in vivo. The binding of RBM15 to c-myc mRNA and m6A modifcation of c-myc mRNA were analyzed. The expressions of METTL3, RBM15 and WTAP were higher in HPV-positive cervical cancer cell lines than those in HPV-negative cells, especially RBM15. HPV-E6 knock-down inhibited the expression of RBM15 protein and promoted its degradation, but couldn't change its mRNA level. Autophagy inhibitor and proteasome inhibitor could reverse those effects. HPV-E6 siRNA could not enhance ubiquitylation modification of RBM15, but could enhance autophagy and the co-localization of RBM15 and LAMP2A. RBM15 overexpression could enhance cell proliferation, block the inhibitory effects of HPV-E6 siRNA on cell growth, and these effects could be reserved by cycloeucine. RBM15 could bind to c-myc mRNA, resulting in an increase to m6A level and protein expression of c-myc, which could be blocked by cycloeucine. HPV-E6 can downregulate autophagy, inhibit the degradation of RBM15 protein, induce the accumulation of intracellular RBM15, and increase the m6A modification on c-myc mRNA, resulting in an increase of c-myc protein and a growth promotion for cervical cancer cells.
基金：
National Natural Science Foundation of China [82002727, 82072862, 82072863, 82172883, 82272949]
第一作者机构：[1]Department of Dermatovenereology, The Seventh Affiliated Hospital, Sun Yat‐sen University, Shenzhen, Guangdong, P. R. China
共同第一作者：
通讯作者：
通讯机构：[*1]Department of Dermatovenereology, The Seventh Affiliated Hospital, Sun Yat‐sen University, Shenzhen, Guangdong 518107, P. R. China.
推荐引用方式(GB/T 7714)：
Nie Gang,Tang Bo,Lv Mingfen,et al.HPV E6 promotes cell proliferation of cervical cancer cell by accelerating accumulation of RBM15 dependently of autophagy inhibition[J].CELL BIOLOGY INTERNATIONAL.2023,47(8):1327-1343.doi:10.1002/cbin.12020.
APA：
Nie, Gang,Tang, Bo,Lv, Mingfen,Li, Danyang,Li, Tian...&Wen, Juan.(2023).HPV E6 promotes cell proliferation of cervical cancer cell by accelerating accumulation of RBM15 dependently of autophagy inhibition.CELL BIOLOGY INTERNATIONAL,47,(8)
MLA：
Nie, Gang,et al."HPV E6 promotes cell proliferation of cervical cancer cell by accelerating accumulation of RBM15 dependently of autophagy inhibition".CELL BIOLOGY INTERNATIONAL 47..8(2023):1327-1343
