| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 100 === The Rab proteins have been reported to be involved in cancer cell motility through their influence on growth factor receptor trafficking and signaling. However, there is little data available on the expression of Rab5A in human breast cancer or its impact on disease progression.
First, the expression of Rab5A was evaluated in breast cancer specimens provided by the Surgery Residual Tissue Bank of the Taipei Veterans General Hospital, Taiwan, by immunohistochemical staining. Then the relationship between the expression of Rab5A and the clinicopathological parameters was analyzed. The increased expression of Rab5A protein in 123 breast cancer samples was associated with higher histological grade (p= 0.004), more lymphovascular invasion (p= 0.027), more axillary lymph node metastasis (p= 0.008), and the higher number of axillary lymph nodes metastasis (p= 0.043). Among 218 axillary lymph nodes of more than 10 nodes metastatic breast cancer patients, all the 167 metastatic lymph nodes were found to have increased expression of Rab5A. The Rab5A protein is associated with the axillary lymph node metastasis in breast cancer patients.
Then the functional role of Rab5A was further examined in breast cancer cells model. The expression of Rab5A in MDA-MB-231 and SK-BR-3 cells can be stimulated by epidermal growth factor (EGF) in a dose-dependent manner. The EGF-induced increase of Rab5A expression correlated well with the enhanced migration ability by wound healing migration assay in MDA-MB-231 breast cancer cells.
Furthermore, knocking down of Rab5A protein function was performed by siRNA and stable clones methods. It was found that after knocking down the expression of Rab5A by siRNA, transwell migration ability decreased in MDA-MB-231 and SK-BR-3 breast cancer cells. Comparison of the MDA-MB-231 control cells with the stable clones of Rab5A knockdown cells revealed that the expression of c-Met and phosphorylated Src was decreased in Rab5A knockdown cells. Migration ability was not increased after stimulation with hepatocyte growth factor in Rab5A-knockdown MDA-MB-231 stable clones as compared to controls.
This study provided evidence that Rab5A plays a role in axillary lymph nodes metastasis and is involved in breast cancer cell migration through the EGF and c-Met signaling pathways. Therefore, targeting Rab5A by itself, or in combination with the EGF or c-Met signaling pathway, may have potential for treatments for breast cancer patients in the future.
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