PMP22蛋白通过促进肿瘤干细胞特性增强胃癌细胞耐药能力

Drug resistance of cancer cells is the major cause of chemotherapy failure and recurrence of cancer. More severely, cancer cells with drug resistance usually develop characteristics of cancer stem cell, with a mechanism poorly understood. In previous research, we treated nude mouse that had gastric cancer with chemotherapy to enrich for drug resistant gastric cancer cells, from which we screened and identified a protein related to drug resistance of cancer cells, which was named PMP22. Our preliminary studies suggested PMP22 could not only enhance drug tolerance of gastric cancer cells, but also contribute to the gastric cancer stem cell behavior, and enhance the expression of SOX2 but those proteins related to drug resistance.These results suggest that PMP22 plays an important role in drug resistance of gastric cancer cell by regulating the characteristics of cancer stem cell. In this proposal, we intend to use techniques spanning molecular, cellular and animal levels, and analysis the clinical samples, by which study we seek to understand the role of PMP22 in gastric cancer drug resistance and cancer stem cell characteristics. Further, we want to demonstrate PMP22 is a signature protein of drug resistance in gastric cancer cell and gastric cancer stem cell, and understand the underlying molecular mechanism during the process including the regulation of PMP22. In addition, we would try to target PMP22 during gastric cancer chemotherapy, and explore the future application of using PMP22 as a chemotherapy target when treating cancer.

耐药性是肿瘤化学治疗失败、肿瘤复发的主要原因,且肿瘤耐药细胞具有肿瘤干细胞的特性，但其调控机制尚未完全阐明。我们前期在裸鼠体内化疗富集胃癌耐药细胞，并筛选出与耐药相关的蛋白PMP22。前期研究发现PMP22能够增强胃癌细胞的耐药性,进一步研究发现PMP22上调SOX2蛋白而不是耐药相关蛋白的表达水平，PMP22表达水平与肿瘤干细胞特性正相关。这些结果表明PMP22可能通过调控肿瘤干细胞特性在胃癌细胞耐药中发挥重要作用。在本项目中，我们拟采用一系列分子、细胞生物学和动物实验，并检测分析临床病例，阐述PMP22与胃癌细胞耐药、肿瘤干细胞特性的关系，进一步探讨PMP22作为胃癌耐药细胞与胃癌干细胞标志蛋白的可行性，并揭示PMP22在此生物学过程中的作用及机制，以及自身所受到的调控机制。此外，我们尝试在化疗方案中以PMP22为分子靶点进行干预，研究PMP22作为化疗靶点在胃癌化学治疗中的应用前景。

肿瘤干细胞在肿瘤的发生、发展、耐药和复发过程中起到关键作用。本项目在裸鼠荷瘤模型中通过顺铂连续化疗方案成功富集了胃癌耐药细胞以及胃癌干细胞，并用高通量蛋白芯片检测差异表达蛋白，筛选出细胞表面蛋白PMP22在化疗组肿瘤标本中表达显著上升。进一步在胃癌细胞中证实，PMP22可作为胃癌干细胞的标志物，通过流式细胞仪分选PMP22表达阳性胃癌细胞可实现胃癌干细胞的富集。同时，在胃癌细胞中改变PMP22的表达可影响胃癌细胞的自我更新能力、耐药能力以及成瘤能力等肿瘤干细胞特性；胃癌临床标本检测结果显示，PMP22在胃癌患者肿瘤组织中表达上调与患者接受常规化疗后的2年复发率正相关，提示PMP22表达水平可用于胃癌化疗的预后评估。最后，本项目建立了以PMP22为靶点的肿瘤治疗方案，即常规化疗联合PMP22抑制药物的新型化疗方案，在胃癌细胞水平以及裸鼠荷瘤模型活体水平中取得良好的治疗效果，为胃癌化疗提供新的靶点和策略。