外泌体MALAT1在M2型巨噬细胞调控胰腺癌放疗抵抗中的作用及机制研究

Pancreatic cancer has a high recurrence rate and poor prognosis. In the clinic, radiotherapy has been widely applied for pancreatic cancer treatment. However, the outcome is not satisfied because of radioresistance. Understanding the underlying mechanism and developing effective strategies for radioresistance are urgently desired. Our previous studies have discovered the interactions between pancreatic cancer cells after radiation lead to radioresistance. But it was far from enough. Therefore, this study will further explore the interactions between cells in the tumor microenvironment of pancreatic cancer after radiation. Through using recombinant DNA technology, fluorescent labeling and FISH, firstly, this study tries to elucidate that exosome-transmitted MALAT1 from M2 macrophage can promote radioresistance in pancreatic cancer. Secondly, this study will further explore whether MALAT1 can competitively inhibit miR-494 to facilitate CCND2 and CDK6 expression, leading to radioresistance. Further, this study tends to reveal that MALAT1 may be an effective target for inhibiting pancreatic cancer cell radioresistance through intervention study. In addition, it is aimed to investigate whether M2 macrophage infiltration and MALAT1 can serve as the mark for predicting radioresistance in clinic. These results may provide scientific basis for targeted intervention of pancreatic cancer cell radioresistance.

胰腺癌是消化道恶性肿瘤，复发率高，预后差。尽管目前放疗在胰腺癌治疗中取得一定疗效，但是疗效有限，放疗抵抗是导致治疗失败的根本原因。因此，阐明胰腺癌放疗抵抗的分子机制及逆转方法显得尤为重要。本课题长期从事肿瘤微环境中免疫细胞与癌细胞间的相互作用在放疗敏感性中作用研究。在充分的文献调研和前期预实验结果的基础上，本课题拟运用基因重组、荧光标记、FISH等技术，阐明胰腺肿瘤微环境中M2型巨噬细胞通过分泌外泌体来源的MALAT1到达胰腺癌细胞，进而竞争性抑制miR-494，从而使CCND2和CDK6表达上调，促进胰腺癌放疗抵抗的分子机制，进而以MALAT1为靶标进行干预，揭示MALAT1可能是抑制放疗抵抗的有效靶点。此外，本课题还将探讨M2型巨噬细胞浸润和MALAT1作为临床预测胰腺癌细胞放疗抵抗的指标的可行性。通过本项研究，将为临床精准提高胰腺癌细胞放疗效果提供理论和实验依据。

胰腺癌是消化道恶性肿瘤，预后极差。尽管目前放疗在胰腺癌治疗中取得一定疗效，但是疗效有限，放疗抵抗是导致治疗失败的根本原因。因此，阐明胰腺癌放疗抵抗的分子机制尤为重要。糖尿病在癌症的进展中起着积极的作用，高血糖记忆是糖尿病促癌作用中的重要影响因素。然而关于高血糖记忆在胰腺癌症放疗抵抗中的作用的研究有限。因此，本课题组研究了高血糖记忆、Numb和二甲双胍在胰腺癌放疗抵抗中的作用及其机制。本课题组在体外和体内建立高糖和高血糖记忆模型，发现低表达Numb可通过高血糖记忆的作用促进胰腺癌放疗抵抗，然而体内外的研究表明二甲双胍可通过激活Numb从而抑制胰腺癌放疗抵抗。此外，PLK1和Notch信号通路（Notch1，HEY1）在高血糖记忆诱导的胰腺癌放疗抵抗中表达出现升高。过表达Numb或二甲双胍的应用可以抑制Notch通路，从而减轻胰腺癌的放疗抵抗。本课题组的数据表明Numb可能是改善高血糖记忆损伤的一个有希望的靶点，二甲双胍在抑制胰腺癌放疗抵抗中的作用值得关注。