CD44 对前列腺癌放射敏感性的调节作用及机制研究

The study of radioresistance of prostate cancer is one of the most hot topics in radiation oncology. Cancer stem cell is regarded as the cause of radioresistance and CD44 has been proved to be the marker of prostate cancer stem cell. For the first time, we found that overexpression of CD44 is related with the radioresistence of prostate cancer cell lines in vitro and in vivo. Radiosensitivity of prostate cancer cells could be enhanced using CD44 silencing technique. Our further study revealed that CD44 protein co-expresses and interacts with ErbB2 in prostate cancer cells and increase the stability of ErbB2 protein. As ErbB2 plays an important role in the surviving mechanism of cancer cells to X-ray irradiation, we would like to use the in vitro and in vivo model to study the regulating effect and mechanism of CD44/ErbB2 signaling pathway in the radiosensitivity of prostate cancer cells, and futher test the p-ErbB2, p-AKT,p-MAPK, p-Stat3,p-Chk1, p-Chk2, NF-κB, c-myc, Survivin and rH2AX which are regulated by ErbB2. Finally, we would like to test the CD44, ErbB2, p-ErbB2, p-AKT,p-MAPK, p-Stat3,p-Chk1, p-Chk2, NF-κB, c-myc, Survivin and rH2AX in human prostate cancer tissues to figure out the prognostic significance of CD44/ErbB2 signaling pathway in prostate cancer patients underwent definitive radiotherapy, aiming to finding molecular markers for predicting recurrence and targets for radiosensitization.

前列腺癌放射抗拒的分子机制是目前放射肿瘤学领域的研究热点。研究表明肿瘤干细胞是肿瘤对治疗抗拒的根源，CD44是前列腺癌干细胞的标记物。本课题组首次发现：①下调CD44表达增加前列腺癌细胞体内外的放射敏感性；②CD44高表达与前列腺癌患者放疗后生化复发相关；进一步研究发现：③CD44与ErbB2呈共表达状态并相互作用，CD44可增加ErbB2蛋白的稳定性；④文献显示ErbB2在细胞耐受X射线的过程中具有重要作用。因此，本课题拟进一步应用体内外实验模型探讨CD44/ErbB2信号通路对前列腺癌放射敏感性的调节作用；检测CD44对ErbB2下游相关蛋白的影响，阐明CD44/ErbB2信号通路调节放射敏感性的机制；最后在人前列腺癌标本中检测CD44/ErbB2信号通路相关蛋白的表达，分析其预后价值，从而揭示CD44对前列腺癌放射敏感性的调节作用和机制，为前列腺癌放疗提供疗效预测指标和放射增敏靶点。

前列腺癌是常见的男性泌尿系肿瘤，近年来，我国前列腺癌的发病率和死亡率亦上升趋势，严重威胁男性的健康。放射治疗外照射的剂量与前列腺癌的肿瘤局部控制率呈正相关关系但放疗剂量的增加使得放疗并发症的概率相应增加，可能给前列腺癌患者带来更多急性和晚期毒性。临床结果显示高剂量的精确放疗仍然无法完全克服前列腺癌对放射抗拒这一问题，从放射生物学的角度着手，探索研究前列腺癌放射抗拒相关的分子机制，最有望突破当前前列腺癌放射治疗的瓶颈，具有重要的临床价值和社会意义。.我们的研究发现CD44阳性的前列腺癌细胞对射线更为抗拒，经典的CD44/HA信号通路无法解释其内在机理，因此选择从CD44和ERBB2的共表达阐述机理。结果显示CD44和ERBB2蛋白呈现共表达，CD44的下调影响ERBB2蛋白的稳定性，加速ERBB2蛋白降解。放射照射激活CD44/ErbB2下游的p-38磷酸化，从而促进肿瘤细胞损伤修复。射线激活CD44/ErbB2下游的p-38磷酸化后，主要调控了同源重组修复这条信号通路，对DNA双链断裂这种最严重的放射所致损伤进行有效的修复。ERBB2受体抑制剂或p-38激酶抑制剂均可以阻断CD44和ERBB2共表达介导的放射抗拒信号通路，有望在今后的研究中进一步探索是否可采用这些药物在前列腺癌中达到放射增敏的目的。