c-myc转录调控宫颈鳞癌干细胞特性的分子机制及化学干预策略研究

Cervical cancer is the second most common cancer in women worldwide, and became a serious public health problem now. In recent years, studies on gene transcription get great attention, as one of the core processes in the central dogma, the chemical intervention of gene transcription via small molecules has been one of the strategies for anticancer drug design.From 1960s, the cancer stem cell (CSC) theory is booming, cervical cancer stem cell (CCSC) is recognized as being the ‘seed’ for cancer metastasis. However, the transcriptional regulation of c-myc haven’t be connected with CCSCs, and the anti-tumor drugs that regulate the plasticity of CCSCs via c-myc transcription haven’t been discovered. Our previous studies found that c-myc transcription regulated the growth of cervical squamous cancer cells, drugs that down-regulate the transcription of c-myc could fight against cervical squamous cell carcinoma. .This application is presented based on the results of our previous studies and papers. We proposed to identify and separate CCSCs from Cervical squamous carcinoma tissues, and investigate the molecular mechanisms of regulating the plasticity of CCSCs via c-myc transcription by using some recognized inhibitors of c-myc transcription. Based on these fundamental results, we expect to discover small molecules to regulate the transcription of c-myc in CCSCs, at the same time, illuminate the mechanisms of how the molecules work so as to uncover the scientificity and feasibility of this novel anti-tumor strategy. The implement of this application could enrich and complete the molecular biological and cytobiological theory of CCSCs, meanwhile, provide the theoretical and experimental basis for drug discovery on cervical cancer treatment based on gene transcription.

宫颈癌是危害女性健康的重大疾病，常伴随着基因的异常转录，基于基因转录的化学干预是抗宫颈鳞癌药物设计的策略之一。宫颈鳞癌干细胞是宫颈鳞癌发生发展的“种子”，c-myc对肿瘤干细胞特性的诱导和维持至关重要。但c-myc转录与宫颈鳞癌干细胞特性的维持机制是否相关尚不清楚，基于此调控机制的化学干预策略尚未发展。我们的前期研究发现，多种调控元件参与宫颈鳞癌细胞中的c-myc转录过程，化学定向干预可下调c-myc转录而抗击肿瘤。本项目利用代表性的c-myc转录抑制剂为工具，通过分子生物学和化学生物学手段，研究宫颈鳞癌干细胞中c-myc转录调控的分子机制，这对于丰富和完善肿瘤干细胞的分子和细胞生物学研究有着重要意义。在此基础上，我们还将从FDA药物库中筛选调控宫颈鳞癌干细胞中c-myc转录的药物先导物，可为开发新型抗肿瘤药物提供理论基础和实践指导。

宫颈癌是危害女性健康的重大疾病，常伴随基因的异常转录。宫颈鳞癌干细胞是宫颈鳞癌发生发展的种子，c-myc对肿瘤干细胞特性的维持至关重要，但c-myc转录与宫颈鳞癌干细胞特性的维持机制是否相关尚不清楚，基于此调控机制的化学干预策略尚未发展。本项目希望阐明宫颈鳞癌干细胞中c-myc转录调控的功能和分子机制。在此基础上，从FDA药物库中筛选调控宫颈鳞癌干细胞中c-myc转录的药物先导物。通过我们的研究，成功分离得到了宫颈鳞癌干细胞。在宫颈鳞癌干细胞中， 我们发现NM23-H2是c-myc转录的正向调控因子，二者通过c-myc启动子区域G-四链体形成序列发生相互作用，从而调控c-myc转录和宫颈鳞癌干细胞特性。进一步地，我们从FDA药物库中筛选到了两个NM23-H2-c-myc抑制剂，可抑制c-myc转录和宫颈鳞癌干细胞的干性、增殖和迁移能力。另外，我们还对环状RNA与其他生物大分子的互作功能及机制进行了探索。本项目对于丰富和完善肿瘤干细胞的分子和细胞生物学研究有着重要意义，可为开发新型抗肿瘤药物提供理论基础和实践指导。