Abstract 4916: E3 ubiquitin ligase Cbl-b prevents tumor metastasis by maintaining the epithelial phenotype in multiple drug-resistant gastric and breast cancer cells

Abstract

Abstract Background: Multiple drug resistance (MDR) and metastasis are two major unfavorable factors causing failure of cancer treatment. However, the relationship between MDR and metastasis is not characterized. Additionally, the role of the E3 ubiquitin ligase Cbl-b in metastasis of MDR gastric and breast cancer is little known. Methods: The effect of Cbl-b on tumor invasion and metastasis was analyzed in P-gp-positive gastric adenocarcinoma tissues. Transfections of Cbl-b WT and epidermal growth factor receptor (EGFR) WT plasmid were used to assess Cbl-b and EGFR involvement in epithelial-mesenchymal transition (EMT) and tumor metastasis. Results: MDR gastric and breast cancer cells possess a typical mesenchymal phenotype and an enhanced cell migration capacity. Additionally, Cbl-b is poorly expressed in MDR gastric and breast cancer cells. We performed immunohistochemical analysis on P-gp-positive gastric adenocarcinoma tissues and identified associations between Cbl-b expression and clinical pathological parameters. Gastric cancer patients with low Cbl-b expression were more likely to have tumor invasion (P=0.016) and lymph node metastasis (P=0.007). Moreover, over-expression of Cbl-b reduced cell migration in MDR cell cultures both in vitro and in vivo. Cbl-b over-expression also prevented EMT by inducing ubiquitination and degradation of EGFR, leading to inhibition of the EGFR- ERK/Akt-miR-200c-ZEB1 axis. However, further over-expression of EGFR on a background of Cbl-b over-expression restored both the mesenchymal phenotype and the cell migration capacity of MDR gastric and breast cancer cells. Conclusions: 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. Note: This abstract was not presented at the meeting. Citation Format: Ling Xu, Xiujuan Qu, Ye Zhang, Xiaofang Che, Tianshu Guo, Ying Cai, Aodi Li, Danni Li, Ce Li, Ti Wen, Yibo Fan, Kezuo Hou, Yanju Ma, Xuejun Hu, Yunpeng Liu. E3 ubiquitin ligase Cbl-b prevents tumor metastasis by maintaining the epithelial phenotype in multiple drug-resistant gastric and breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4916. doi:10.1158/1538-7445.AM2017-4916