基于表观遗传修饰调控RARβ2介导的HPV转化细胞分化的作用机制

高危型人乳头瘤病毒(HR-HPV)感染子宫颈上皮储备细胞，使其分化成熟受阻，进入异常细胞周期，导致细胞转化以致形成宫颈癌。组蛋白脱乙酰化酶（HDAC）通过表观遗传修饰抑制正常功能基因的转录是HR-HPV感染细胞发生恶性转化的重要分子事件，因此，HDAC抑制剂（HDACi）作为一种新型靶向抗肿瘤药物而成为研究热点。RARβ2是上皮细胞维持正常分化程序的关键分子，也是一种重要的抑癌基因，在HR-HPV转化细胞其表达被抑制。课题组前期的研究发现，丙戊酸钠（VPA）能够显著提高子宫颈癌细胞RARβ2表达，与ATRA协同诱导肿瘤细胞分化而发挥抗肿瘤作用。在此基础上，课题组将进一步探讨HDACi调控RARβ2表达的分子机制，研究HDACi联合ATRA对不同病变时期HR-HPV转化细胞诱导分化作用，并阐明其重启转化细胞正常分化程序的调控节点，为阻断和/或逆转子宫颈癌前病变及子宫颈癌的治疗提供新的策略。

The cervical epithelial reserved cells (CERC) infect with high-risk human papillomvirus (HR-HPV), which leads to differentiation blockade and abnormal cell cycle after viral genome integrates into host genome, resulting squamous meteplasia, cervical intraepithelial neoplasia (CIN), and cervical carcinoma seriatim. Histone deacetylases (HDAC) binding to the promoters of specific genes and inhibiting these genes transcription via epigenetic modulation are the important molecular events in the process of cervical carcinogenesis induced by HR-HPV. HDAC inhibitors (HDAVi), therefore, have emerged as the potential therapeutic agents for multiple human cancers. RARβ2, as a tumor suppressor gene, play an important role in differentiation of epithelial cells, but is silent in HR-HPV transformed cells. Our previous data show that valproic acid (VPA) combined with all-trans retinoic acid (ATRA) can restore RARβ2 expression, resulting in enhanced anti-neoplastic activity in cervical cancer. In this study, we will investigate the efficiency of differentiation induced by VPA and ATRA in HR-HPV transformed cells with variant grade, and further explore the potential molecular mechanism. All of these results will probably offer a new therapeutic strategy for cervical cancer patients.