抑癌基因ESE3/EHF抑制胰腺癌干性能力的机制研究及临床转化

高复发转移率及化疗抵抗是临床胰腺癌治疗中的重要难题。其产生的最主要原因之一是胰腺癌具有较强的干性能力。申请人近期在J Exp Med上报导了ESE3/EHF在胰腺癌中的抑癌作用，其表达的降低能够引起胰腺癌免疫微环境抑制，促进肿瘤进展。我们进一步研究发现ESE3/EHF表达减低能够显著诱导胰腺癌肿瘤干细胞比例的增加，与化疗抵抗密切相关。通过对190种临床常用药物的筛选，我们发现PPARγ激动剂吡格列酮能够显著上调ESE3/EHF的表达，进而抑制胰腺癌干性和化疗抵抗。本课题将从临床资料分析、细胞功能实验、分子机制研究及动物实验方面开展，拟明确ESE3/EHF低表达与胰腺癌干性表型及化疗耐药的关系，并挖掘其具体分子机制。同时，针对ESE3/EHF上游开展转化研究，探索吡格列酮通过上调ESE3/EHF表达逆转胰腺癌干性能力及化疗耐药的有效性及其分子机制，为临床胰腺癌的治疗提供新策略。

Pancreatic cancer has a high rate of local recurrence and chemoresistance, which is the major challenge for its clinical treatment. Accumulating evidence demonstrated that cancer stem cells are responsible for pancreatic cancer recurrence and chemoresistance. We recently reported on J Exp Med that ESE3/EHF is a critical tumor suppressor in pancreatic cancer. Low expression of ESE3/EHF in pancreatic cancer promoted tumor immune suppression, which furtherly induced tumor progression. Our further research found that low expression of tumoral ESE3/EHF significantly upregulated pancreatic cancer stemness, which was significantly correlated with chemoresistance. Meanwhile, 190 kinds of commonly used medicine in clinical practice were screened for those which can induce ESE3/EHF overexpression in our research. PPARγ agonist pioglitazone was identified as the one which can inhibit cancer stemness and chemoresistance by significantly upregulating the expression of ESE3/EHF. Based on our previous work, this investigation will be conducted to elucidate the function and mechanism of ESE3/EHF in regulating cancer stemness and chemoresistance. As ESE3/EHF may be a promising target for pancreatic cancer therapy, the translational study will be conducted to explore the function and mechanism of pioglitazone in inhibiting pancreatic cancer stemness and chemoresistance by upregulating the expression of ESE3/EHF. This project would provide the theoretical basis for the development of new strategies for pancreatic cancer therapy.