PMP22 Regulates Self-Renewal and Chemoresistance of Gastric Cancer Cells.
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 cisplatinin vitroand 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.Mol Cancer Ther; 16(6); 1187-98. ©2017 AACR.
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.|Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Wangyu
W
Cai
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.|Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Gang
G
Chen
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.|Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Qicong
Q
Luo
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.|Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Jun
J
Liu
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.|Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Xiaofeng
X
Guo
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.|Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Tian
T
Zhang
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.|Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Fei
F
Ma
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China.|Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Liang
L
Yuan
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. jianchunfh2@sina.com bali@xmu.edu.cn.
Boan
B
Li
Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian, China. jianchunfh2@sina.com bali@xmu.edu.cn.|Institute of Gastrointestinal Oncology, Medical College of Xiamen University, Xiamen, Fujian, China.
Jianchun
J
Cai
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D034622:RNA Interference; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009185:Myelin Proteins; C073687:PMP22 protein, human