VDR介导的KLF4信号激活在逆转胰腺癌肿瘤干细胞耐药中的机制研究

Pancreatic cancer is marked with poor prognosis as the reason of drug resistance. It has been confirmed that cancer stem cells (CSC) are the initiating agent leading to drug resistance. However, the exact mechanism of the current regulation of CSC and drug resistance remains to be elucidated. Our previous experiments showed found that KLF4 plays a key role in the development and homeostasis of pancreatic cancer, and is also one of the important regulation factors involved in CSCs characteristics and functions (Cancer Cell.2016; CR.2016; CCR.2015). Our preliminary experiment confirmed that VDR could enhance the sensitivity of gemcitabine chemotherapy and regulate the expression of KLF4 and CSCs phenotypic proteins, thereby enhancing chemoresistance and CSC-like properties. KLF4 promotor analysis and co-immunoprecipitation have shown that VDR could regulate KLF4 gene at the both levels of transcription and translation. Based on the above proposed scientific assumptions: VDR reduces the pancreatic cancer stemness and ultimately reverses the drug resistance probably through the activation of KLF4 signal and inhibition of CSC phenotypic gene expression.This study commit to elucidate the significant regulatory role of VDR-KLF4 gene signaling in CSC- induced pancreatic cancer drug resistance pathway from three aspects: gene function, activation of signal transduction mechanism and drug resistance regulation, so as to develop appropriate treatment strategies for pancreatic cancer and open up a new therapy path aiming at CSC critical signaling pathways and corresponding targets.

耐药是晚期胰腺癌治疗失败的主因，但机制不清。研究表明肿瘤干细胞（CSC）可能是导致耐药的始动因素，然而目前调控CSC与耐药的确切分子机制仍有待阐明。我们前期发现KLF4基因参与胰腺癌的进程，显著调控胰腺癌干性特征(Cancer Cell.2016; CR.2016; CCR.2015)。近期我们预实验证实VDR可增强吉西他滨的药敏，调控KLF4和CSC表型标记蛋白的表达，影响胰腺癌干性特征，经检索KLF4启动子及免疫共沉淀发现VDR在转录和翻译后两个层面均可能调控KLF4基因功能。基于上述提出科学假设：VDR可能通过激活KLF4信号，抑制CSC表型基因表达，降低胰腺癌干性特征，最终逆转耐药。该项目拟从基因功能、活化信号转导机制和耐药调控三方面阐明VDR-KLF4在CSC导致胰腺癌耐药信号通路中的重要调控作用，从而针对CSC关键信号通路和靶点制定相应的治疗策略，探寻逆转耐药治疗的新方向。

胰腺癌是一种高致死性肿瘤，主要原因是诊断晚、早期转移和耐药性强等。VDR在肿瘤细胞及肿瘤微环境调控方面，仍存在一定争议。对本项目经过多次探索实践，进一步明确了VDR在胰腺癌中的调控作用及在胰腺癌免疫微环境中发挥调控作用，VDR在胰腺癌中调控机制的认识提供新的理论基础。本项目取得了阶段性的研究成果，分析了VDR在胰腺癌中发挥抑癌作用的分子机制，明确了 VDR 下游调控分子。同时，课题还探讨了 VDR 与免疫浸润的关系，调控微环境的功能意义，同时炎症反应作为肿瘤的重要特点之一，我们发现全身炎症标志物纤维蛋白原与白蛋白比率（FAR）、单核细胞与淋巴细胞比率（MLR）、中性粒细胞与淋巴细胞比率（NLR）和血小板与淋巴细胞比率（PLR）可作为预测胰腺癌患者预后的潜在指标。本课题完善了对VDR在胰腺癌分子功能认识，为抗肿瘤治疗和预防提供重大的临床意义。