研究资料显示抑癌基因ARID1A在宫颈癌中表达缺失，且其功能缺失与宫颈癌恶性进展相关，但其在宫颈癌中表达缺失及抑癌机制尚不清楚。本项目前期研究发现在宫颈癌细胞中IKKβ与ARID1A有相互作用并在转录后水平抑制ARID1A表达；ARID1A结合在SUFU启动子并上调其转录。本项目拟在此基础上从分子、细胞、组织和动物水平：阐明IKKβ磷酸化ARID1A以及βTRCP介导的ARID1A泛素化降解是宫颈癌中ARID1A表达缺失的重要机制之一；确定ARID1A通过SWI/SNF染色质重塑活性上调SUFU表达来抑制Hedgehog通路是ARID1A抑制宫颈癌发生发展的机制之一；阐明TNFα和Hedgehog通路在宫颈癌中通过TNFα/IKKβ/ARID1A/SUFU/Hh这条新通路来交叉调控，共同促进宫颈癌恶性进展。以上问题的解决，将为宫颈癌的诊断和发现治疗性靶标提供理论基础和实验依据。

Evidences have shown that loss of ARID1A protein expression in the cervical cancer is related to malignant progression of the cancer.But the molecular mechanism involved in ARID1A expression deletion and its tumor suppressor function remain to be elucidated. Previously we found that IKKβ interacts with ARID1A and inhibits the expression of ARID1A at post-transcription level. Moreover, we found that ARID1A binds to the promoter of SUFU and inhibits the transcription of SUFU. In this study, we will further explore that ARID1A is phosphorylated by IKKβ and subsequently degraded by βTRCP mediated Ubiquitination,which may be a important mechanism of ARID1A loss in the cervical cancer. We will investigate that ARID1A suppresses Hedgehog pathway by upregulating SUFU expression through SWI/SNF mediated chromatin remodelling activity which is a improtant mechanism of ARID1A tumor suppressor function. We will also prove that TNFα crosstalks with Hedgehog pathway through TNFα/IKKβ/ARID1A/SUFU/Hh pathway. This study will help to discover new promising therapeutic approach for the treatment of cervical cancer.