Cai Wangyu, Chen Gang, Luo Qicong, Liu Jun, Guo Xiaofeng, Zhang Tian, Ma Fei, Yuan Liang, Li Boan, Cai Jianchun
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.
Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Mol Cancer Ther. 2017 Jun;16(6):1187-1198. doi: 10.1158/1535-7163.MCT-16-0750. Epub 2017 Mar 23.
Cancer stem cells possess self-renewal and chemoresistance activities. However, the manner in which these features are maintained remains obscure. We sought to identify cell surface protein(s) that mark self-renewing and chemoresistant gastric cancer cells using the explorer antibody microarray. We identified PMP22, a target gene of the Wnt/β-catenin pathway, as the most upregulated cell surface protein in gastric cancer xenografts exposed to cisplatin (DDP). PMP22 expression was markedly upregulated in tumorspheric cells and declined with differentiation. Infecting gastric cancer cells with lentivirus expressing PMP22 shRNAs reduced proliferation, tumorsphere formation, and chemoresistance to cisplatin and in NOD/SCID mice. When combined with bortezomib, a PMP22 inhibitor, the chemotherapeutic sensitivity to cisplatin treatment was dramatically increased by inducing cell apoptosis in cultured cells and xenograft mouse models. Finally, mRNA expression levels of PMP22 were detected in 38 tumor specimens from patients who received six cycles of perioperative chemotherapy. A strong correlation between PMP22 level and tumor recurrence was revealed, thus showing a pivotal role of PMP22 in the clinical chemoresistance of gastric cancer. Our study is the first to show the role of PMP22 in gastric cancer stemness and chemoresistance and reveals a potential new target for the diagnosis and treatment of recurrent gastric cancer. .
癌症干细胞具有自我更新和化疗耐药活性。然而，维持这些特性的方式仍不清楚。我们试图使用探索者抗体微阵列鉴定标记自我更新和化疗耐药胃癌细胞的细胞表面蛋白。我们鉴定出PMP22，一种Wnt/β-连环蛋白通路的靶基因，是暴露于顺铂（DDP）的胃癌异种移植瘤中上调最明显的细胞表面蛋白。PMP22在肿瘤球细胞中表达明显上调，并随分化而下降。用表达PMP22短发夹RNA的慢病毒感染胃癌细胞可降低其增殖、肿瘤球形成及对顺铂的化疗耐药性，在NOD/SCID小鼠中也是如此。当与硼替佐米（一种PMP22抑制剂）联合使用时，在培养细胞和异种移植小鼠模型中，通过诱导细胞凋亡，对顺铂治疗的化疗敏感性显著增加。最后，在接受六个周期围手术期化疗的患者的38个肿瘤标本中检测了PMP22的mRNA表达水平。结果显示PMP22水平与肿瘤复发之间存在强相关性，从而表明PMP22在胃癌临床化疗耐药中起关键作用。我们的研究首次表明PMP22在胃癌干性和化疗耐药中的作用，并揭示了复发性胃癌诊断和治疗的潜在新靶点。
