57111

RAB25

RAB25, member RAS oncogene family;RAB25;RAB25, member RAS oncogene family

ras-related protein Rab-25

1q22

protein-coding

Rab25, an epithelial-specific member of the Rab family of small guanosine triphosphatases, is associated with several human cancers. The goal of this study was to determine its function in bladder cancer (BC). We examined the Rab25 expression pattern in two different cohorts of BC patients treated with radical cystectomy by quantitative PCR, western blotting and immunohistochemical staining. A series of in vitro and in vivo assays were performed to elucidate the function of Rab25 in BC and its underlying mechanisms. Rab25 expression was significantly elevated at both the messenger RNA and protein levels in BCs compared with normal bladder tissues. High Rab25 expression was closely associated with lymph node (LN) metastasis and was an independent predictor for poor disease-free survival in BC patients. Downregulation of Rab25 in BC cells markedly inhibited invasive motility in vitro and metastatic potential in vivo. In addition, downregulation of Rab25 in BC EJ and T24 cells increased the expression levels of epithelial markers (E-cadherin and alpha-catenin) and decreased the levels of mechamechy markers (vimentin and fibronectin). Simultaneously, downregulation of Rab25 in EJ and T24 cells resulted in the inactivation of downstream phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-beta (p-GSK-3beta) and snail signaling. This study demonstrates that Rab25 can promote BC metastasis through induction of epithelial-mesenchymal transition process and activation of Akt/GSK-3beta/Snail signaling pathway; Rab25 expression level can predict LN metastasis and inferior clinical outcome in BC patients.

Breast cancer is the most common cancer in women worldwide. Studies have suggested that Ras-related protein 25 (Rab25), a member of Rab small GTPase family, is involved in the pathogenesis of breast cancer. In this study, we investigated whether the expression of Rab25 correlated with lymphatic metastasis in breast cancer and whether the expression of Rab25 was positively correlated with oestrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer. Breast cancer tissues from 42 invasive ductal breast cancer patients with or without lymphatic metastasis were collected and the levels of Rab25 mRNA and protein measured by quantitative real-time PCR and immunohistochemistry, respectively. The mRNA level of Rab25 was significantly increased in invasive ductal breast cancer with lymphatic metastasis compared to that in invasive ductal breast cancer without lymphatic metastasis. Immunohistochemical analysis demonstrated that Rab25 and vascular endothelial growth factor (VEGF) were highly expressed in invasive ductal breast cancer with lymphatic metastasis regardless of whether the cancer is ER and PR positive or negative. Higher expression of Rab25 positively correlated with VEGF expression. However, the expressions of Rab25 in ER and PR-positive cancers were much higher than ER and PR-negative cancers regardless of whether lymphatic metastasis occurred. These data suggest that higher level of Rab25 was associated with lymphatic metastasis, specifically in ER and PR-positive breast cancer. The better understanding of the mechanism of Rab25 may provide a basis for the development of a novel therapeutic target in breast cancer.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common cancers with a 50% five-year survival rate, which has remained unchanged for the past three decades. One of the major reasons for the aggressiveness of this cancer is that HNSCCs readily metastasize to cervical lymph nodes that are abundant in the head and neck region. Hence, discovering new molecules controlling the metastatic process as well as understanding their regulation at the molecular level are essential for effective therapeutic strategies. EXPERIMENTAL DESIGN: Rab25 expression level was analyzed in HNSCC tissue microarray. We used a combination of intravital microscopy in live animals and immunofluorescence in an in vitro invasion assay to study the role of Rab25 in tumor cell migration and invasion. RESULTS: In this study, we identified the small GTPase Rab25 as a key regulator of HNSCC metastasis. We observed that Rab25 is downregulated in HNSCC patients. Next, we determined that reexpression of Rab25 in a metastatic cell line is sufficient to block invasion in a three-dimensional collagen matrix and metastasis to cervical lymph nodes in a mouse model for oral cancer. Specifically, Rab25 affects the organization of F-actin at the cell surface, rather than cell proliferation, apoptosis, or tumor angiogenesis. CONCLUSION: These findings suggest that Rab25 plays an important role in tumor migration and metastasis, and that understanding its function may lead to the development of new strategies to prevent metastasis in oral cancer patients.

Ovarian cancer is the leading cause of death in gynecological cancer. Studies suggested Rab25 is involved in the pathogenesis of ovarian cancers. We here investigated the expression of Rab25 is in all ovarian cancers and whether the expression of Rab25 is associated with peritoneal metastasis. Fifty-nine ovarian cancer patients were included and the levels of Rab25 measured by immunohistochemistry. Our data showed Rab25 was highly expressed in all subtypes of epithelial ovarian cancers, and two subtypes of germ cell tumors, but not in sex cord stromal tumors. Furthermore, the Rab25 expression was not correlated with peritoneal metastasis of ovarian cancer.