Increased high mobility group A 2 expression promotes transition of cervical intraepithelial neoplasm into cervical cancer

// Liming Wang 1, * , Hui Shen 1, * , Da Zhu 2 , Bei Feng 1 , Lan Yu 1 , Xun Tian 1 , Ci Ren 1 , Chun Gao 1 , Xiaomin Li 1 , Ding Ma 2 , Zheng Hu 3, 2 and Hui Wang 2 1 Key Laboratory of Cancer Invasion and Metastasis of the Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 2 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 3 Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China * These authors contributed equally to this work Correspondence to: Ding Ma, email: dma@tjh.tjmu.edu.cn Zheng Hu, email: 18627803527@163.com Hui Wang, email: huit71@sohu.com Keywords: cervical cancer; cervical intraepithelial neoplasia (CIN); high mobility group A 2 (HMGA2); high-risk human papillomavirus (HR-HPV); apoptosis Received: April 14, 2017      Accepted: January 04, 2018      Published: January 09, 2018 ABSTRACT Integration of the high risk human papillomavirus (HR-HPV) genome into host chromatin is an important step in cervical carcinogenesis. We identified HR-HPV integration sites within the human genome through detection of integrated papillomavirus sequences-PCR and assessed the role of high mobility group A 2 (HMGA2) in cervical carcinogenesis in clinical samples and cell lines. HPV integration sites were analyzed in 40 cervical cancer samples, while copy number variation and protein expression were assessed in 19 normal cervixes, 49 cervical intraepithelial neoplasia (CIN), and 52 cervical cancer samples. Overall, 25 HR-HPV integrating loci were detected in 24 cervical samples; HMGA2 was the only recurring integration site. Both HPV copy number and HMGA2 protein expression were higher in cervical cancer than CIN samples. Area under the curve (AUC) values for HMGA2 expression and HPV copy number were 0.910 (95% CI: 0.844–0.976) and 0.848 (95% CI: 0.772–0.923), respectively. Expression of Bcl-2 and Caspase 3 can indicate the cell proliferation and apoptosis. Transfection of HMGA2 siRNA decreased HMGA2 mRNA and protein expression, Bcl-2 expression, inhibited cell proliferation, and increased Caspase 3 expression and apoptosis in SiHa, CaSki and S12 cervical cancer cells. HMGA2 overexpression had the opposite effects. These results suggest that elevated HMGA2 expression is associated with transformation of CIN into cervical cancer and that HMGA2 might be a useful biomarker for assessing the risk of cervical lesion progression.