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.
Highlights
Cervical cancer, the second most common cancer and the third leading cause of cancer-related death in women worldwide, creates substantial public health and financial burdens in developing countries such as China [1, 2]
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
Recent studies have demonstrated that genomic instability and HPV integration contribute to cervical cancer tumorigenesis
Summary
The second most common cancer and the third leading cause of cancer-related death in women worldwide, creates substantial public health and financial burdens in developing countries such as China [1, 2]. The E6 and E7 oncogenes of HR-HPV, which target the p53 and retinoblastoma (Rb) proteins, respectively, are crucial factors in cervical cancer carcinogenesis. The high mobility group A 2 (HMGA2) protein belongs to a family containing 4 members: HMGA1a, www.impactjournals.com/oncotarget. The human HMGA2 gene contains 5 exons located on the chromosome band 12q13-15 and spanning more than 140 kb. HMGA2 protein directly binds to DNA, modifying its conformation to allow binding of a group of transcriptional factors (TF). The HMGA2 can inhibit tumor cell apoptosis by protecting the telomere [4]. Previous studies have identified HMGA2 as a hot spot gene for HPV integration [5], and it can affect cell apoptosis by exerting opposite influences on Bcl-2 and Caspase 3 [6]
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