Rab11‐FIP2 promotes the metastasis of gastric cancer cells

• Published in: International journal of cancer 2016-04, Vol.138 (7), p.1680-1688
• Main Authors: Dong, Wenjie, Qin, Guohui, Shen, Ruizhe
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Aged; Blotting, Western; Cancer; Carrier Proteins - metabolism; Cell adhesion & migration; Cell Line, Tumor; Cell Movement - physiology; Epithelial-Mesenchymal Transition - physiology; Female; Fluorescent Antibody Technique; Gastric cancer; HIF‐1α; Humans; Hypoxia; Immunohistochemistry; Male; Medical research; Membrane Proteins - metabolism; Metastasis; Middle Aged; Neoplasm Invasiveness - pathology; Polymerase Chain Reaction; rab GTP-Binding Proteins; Rab11‐FIP2; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Tissue Array Analysis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.29899

Rab11‐FIP2 can interact with MYO5B and plays an important role in regulating plasma membrane recycling. Our previous study has shown that MYO5B is epigenetically silenced and associated with c‐Met signaling in human gastric cancer. However, little is known of the function of Rab11‐FIP2 in gastric cancer. In this study, we investigated Rab11‐FIP2 expression by immunohistochemistry in 86 patients with gastric cancer. We found that the expression level of Rab11‐FIP2 was significantly increased in gastric cancer tissues and high expression of Rab11‐FIP2 was closely correlated with nodal metastasis in gastric cancer patients. Rab11‐FIP2 overexpression promoted epithelial–mesenchymal transition (EMT) in a manner associated with gastric cancer metastasis in vitro and in vivo. We also found that hypoxia could enhance the expression of Rab11‐FIP2 through HIF‐1α. Inactivation of Rab11‐FIP2 dramatically decreased hypoxia‐induced migration of gastric cancer cells. Suppression of the internalization of EGFR, at least in part, plays an important role in EMT induced by overexpression of Rab11‐FIP2 in gastric cancer cells. Finally, we demonstrated that Rab11‐FIP2 could regulate actin cytoskeleton dynamics. In conclusion, our findings reveal a novel mechanism underlying the role of Rab11‐FIP2 in gastric cancer dissemination, suggesting that Rab11‐FIP2 may be a promising candidate target for gastric cancer treatment. What's new? Defects in membrane vesicle trafficking are a hallmark of carcinogenesis, and included among them are alterations in membrane vesicle recycling. Central to vesicle recycling are Rab proteins, including Rab11‐FIP2, a functionally enigmatic player. Here, nodal metastasis in gastric cancer patients was found to be closely associated with Rab11‐FIP2 overexpression. Both in vitro and in vivo, Rab11‐FIP2 overexpression promoted gastric cancer cell migration, an effect associated with hypoxia‐induced HIF‐1α expression and Rab11‐FIP2 upregulation. Rab11‐FIP2 gene silencing, on the other hand, greatly restricted hypoxia‐induced cell migration. In addition, in vitro, Rab11‐FIP2 overexpression was found to regulate actin cytoskeleton dynamics.