CD133/Src信号轴在胆囊癌放疗后凋亡细胞增强残存癌细胞浸润的功能及机制研究

Besides its therapeutic effects, radiotherapy also enhance the malignancy of treated cancer cells in clinical situations which is called "accelerated repopulation". This phenomenon, for which little is understood at the molecular level, has played a major part in modern radiotherapy and chemotherapy. Recent research reported that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. During radiotherapy, apoptotic cells release prostaglandin E2 (PGE2), which can potently stimulate growth and invasion of surviving tumor cells by activating Src pathway. Meanwhile, CD133+ cancer stem cells play a critical role in tumor recovery process after treatment and are resistant to radiotherapy depending on Src and Akt pathway. We found that CD133 was highly expressed in gallbladder carcinoma tissue as compared to normal. Inhibiting expression of CD133 by RNAi down-regulates the invasion of gallbladder cancer cells accompanied by the down-regulation of phosphorylation of Src and Akt. Down-regulation of CD133 expression reduced PGE2-induced cell invasion. We propose that the apoptotic cells induced CD133+ gallbladder carcinoma cells invasion at least partly through PGE2/Src/CD133/Akt signaling pathway. This project aimed to study the role and mechanism of how apoptotic cells promoted gallbladder carcinoma cell invasion through CD133/Src signaling axis. Through these efforts, we wish to establish a typical model for the research of apoptotic cells on invasion enhancement of CD133+ gallbladder carcinoma cells.

肿瘤放疗后残癌细胞侵袭性增强的"加速现象"是制约肿瘤治疗的重要临床问题。近几年发现凋亡细胞能促进残癌细胞的增殖，而CD133+肿瘤干细胞被认为是肿瘤中的耐药细胞群，研究凋亡细胞促进CD133+胆囊癌干细胞侵袭的机制，对寻找有效措施以减少放疗后胆囊癌细胞的转移复发有着关键意义。已有的研究证实凋亡细胞能通过释放PGE2激活肿瘤细胞内Src的活性，而CD133与Src、Akt信号通路之间也有着密切的关联。我们前期研究发现CD133在胆囊癌组织中高表达，抑制CD133表达后下调胆囊癌细胞侵袭能力，并伴随着磷酸化Src和Akt的活性下降。并且抑制CD133表达下调PGE2促胆囊癌侵袭作用。本项目以CD133/Src信号轴在凋亡细胞促残癌细胞侵袭中的动态变化和机制为中心，提出PGE2/Src/CD133/Akt这一新的调控途径并明确其功能，有助于我们更加深入、全面地了解放疗后残癌侵袭性增强的分子机制。

本项目重点研究肿瘤放疗后残癌细胞侵袭性增强的"加速现象"这一制约肿瘤治疗的重要临床问题。近几年发现凋亡细胞能促进残癌细胞的增殖，而 CD133+肿瘤干细胞被认为是肿瘤中的耐药细胞群，研究凋亡细胞促进CD133+胆囊癌干细胞侵袭的机制，对寻找有效措施以减少放疗后胆囊癌细胞的转移复发有着关键意义。本项目研究发现CD133 在胆囊癌组织中高表达，并聚集在侵袭区。抑制 CD133 表达后下调胆囊癌细胞迁移、侵袭能力。该作用通过抑制Akt的磷酸化导致。通过基因芯片等发法发现CD133表达下调可以抑制Akt通路的激活因子SDF1基因表达。通过酵母双杂交等发发现CD133和p85、HDAC6、DLC1等蛋白相互作用，其中p85已被证实和CD133相互作用。另外，放疗或者化疗导致的残癌细胞释放PGE2。PGE2通过CD133促进胆囊癌细胞迁移。本项目围绕CD133/Src 信号轴在凋亡细胞促残癌细胞侵袭中的动态变化和机制为中心，提出PGE2/Src/CD133/Akt 这一新的调控途径并明确其功能，有助于我们更加深入、全面地了解放疗后残癌侵袭性增强的分子机制。研究成果发表Oncotarget、Scientific reports杂志。.胆囊癌;放疗;CD133/Src;凋亡细胞;浸润