E3 Ubiquitin Ligase Cbl-b Prevents Tumor Metastasis by Maintaining the Epithelial Phenotype in Multiple Drug-Resistant Gastric and Breast Cancer Cells.
Multiple drug resistance (MDR) and metastasis are two major factors that contribute to the failure of cancer treatment. However, the relationship between MDR and metastasis has not been characterized. Additionally, the role of the E3 ubiquitin ligase Cbl-b in metastasis of MDR gastric and breast cancer is not well known. In the present study, we found that MDR gastric and breast cancer cells possess a typical mesenchymal phenotype and enhanced cell migration capacity. Additionally, Cbl-b is poorly expressed in MDR gastric and breast cancer cells. In MDR gastric adenocarcinoma tissues, gastric cancer patients with low Cbl-b expression were more likely to have tumor invasion (P=.016) and lymph node metastasis (P=.007). Moreover, overexpression of Cbl-b reduced cell migration in MDR cell cultures both in vitro and in vivo. Cbl-b overexpression also prevented EMT by inducing ubiquitination and degradation of EGFR, leading to inhibition of the EGFR-ERK/Akt-miR-200c-ZEB1 axis. However, further overexpression of EGFR on a background of Cbl-b overexpression restored both the mesenchymal phenotype and cell migration capacity of MDR gastric and breast cancer cells. These results suggest that Cbl-b is an important factor for maintenance of the epithelial phenotype and inhibition of cell migration in MDR gastric and breast cancer cells.
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Ling
L
Xu
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Ye
Y
Zhang
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China. Electronic address: xiujuanqu@yahoo.com.
Xiujuan
X
Qu
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Xiaofang
X
Che
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Tianshu
T
Guo
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Ying
Y
Cai
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Aodi
A
Li
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Danni
D
Li
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Ce
C
Li
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Ti
T
Wen
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Yibo
Y
Fan
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Kezuo
K
Hou
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
Yanju
Y
Ma
Department of Respiratory Medicine, the First Hospital of China Medical University, Shenyang 110001, China.
Xuejun
X
Hu
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China. Electronic address: cmuliuyunpeng@hotmail.com.
Yunpeng
Y
Liu
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl