酸性代谢应激诱导的钙稳态重塑在胰腺癌细胞EMT中作用研究

The research indicates that calcium remodeling is correlated with migration and metastasis of tumor. Our previous study showed that pHe was significantly decreased in pancreatic cancer tissues, and the acidity treated pancreatic cells demonstrated EMT with enhanced invasion. Meanwhile, the ASICIα was activated and increased calcium input. Thus, we hypothesis that the acidity induced metabolism stress regulates EMT of pancreatic cancer cells by remodeling the calcium. The presents study will culture pancreatic cancer cells in different pHe and then observe the effects of acidity on invasion of pancreatic cancer cells. Furthermore, the pHe, ASCI Iα，calcium, and EMT related maker were detected with molecular methods. The EMT and invasion of pancreatic cancer cells will be evaluated both in vitro and in vivo after regulated in different pathway. As the starting point of the regulatory role of the acidic stress on EMT of pancreatic cancer, the present study will investigate the effects of acidity on metastasis of pancreatic cancer in chemical-biology transferring scope, which may provide novel target for treatments of pancreatic cancer.Moreover,the study will provide new sight into the tumoregenesis of cancer.

研究表明钙稳态重塑与肿瘤细胞迁移和侵袭密切相关。课题组发现胰腺癌组织pH值显著下降，且胰腺癌细胞在酸性环境培养时发生上皮间质化（EMT），表现为细胞变形和显著增强的侵袭转移。与此同时，酸敏感通道ASCI 1α活化导致Ca2+大量内流。由此推测，酸性代谢应激可能通过重塑钙稳态参与调控胰腺癌细胞EMT过程。拟建立不同酸度培养细胞模型及胰腺癌动物模型，观察酸性代谢应激对侵袭转移的调控；通过膜片钳及细胞内钙成像技术检测细胞外pH值（pHe）-ASCI Iα-细胞内钙稳态-EMT相关信号通路改变；通过药物或基因干预上述通路，观察胰腺癌细胞生物学行为的改变。本课题以酸性代谢应激诱导胰腺癌细胞EMT为切入点，从化学信号-生物信号转换的角度，探讨酸性微环境在胰腺癌恶性生物学行为中的作用机制，为胰腺癌的防治研究提供新靶点，有助于深入理解微环境对肿瘤细胞生物学行为的调控作用。并为恶性肿瘤防治研究提供新思路。

研究表明钙稳态重塑与肿瘤细胞迁移和侵袭密切相关。课题组发现胰腺癌组织 pH 值显著下降，且胰腺癌细胞在酸性环境培养时发生上皮间质化（EMT），表现为细胞变形和显著增强的侵袭转移。与此同时，酸敏感通道 ASCI 1α 活化导致 Ca2+大量内流。由此推测，酸性代谢应激可能通过重塑钙稳态参与调控胰腺癌细胞 EMT 过程。拟建立不同酸度培养细胞模型及胰腺癌动物模型，观察酸性代谢应激对侵袭转移的调控；通过膜片钳及细胞内钙成像技术检测细胞外 pH 值（pHe）-ASCI Iα -细胞内钙稳态-EMT 相关信号通路改变；通过药物或基因干预上述通路，观察胰腺癌细胞生物学行为的改变。本课题以酸性代谢应激诱导胰腺癌细胞EMT 为切入点，从化学信号-生物信号转换的角度，探讨酸性微环境在胰腺癌恶性生物学行为中的作用机制，为胰腺癌的防治研究提供新靶点，有助于深入理解微环境对肿瘤细胞生物学行为的调控作用。并为恶性肿瘤防治研究提供新思路。