Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK-Raf-MEK1/2-ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment. Cancer Res; 72(22); 6024-35. Ó2012 AACR.

CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer

“…We hypothesized that CLIC3 might promote an invasive phenotype similar to that observed in Rab25-expressing ovarian tumors (Dozynkiewicz et al, 2012). However, although Rab25 has been identified as the driver of the 1q22 amplicon, which promotes ovarian cancer aggressiveness (Cheng et al, 2004), it appears to inhibit progression in several other tumor types (Amornphimoltham et al, 2013;Nam et al, 2010;Tong et al, 2012). In ER-negative breast cancer, loss of Rab25 is common (Cheng et al, 2006).…”

Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

“…Through mass spectrometric (MS) analysis, heat-shock protein 90a has been identified as a component of Rab27B-regulated vesicles and it acts as a pro-invasive growth regulator required for MMP2 activation 6 . Previous studies indicate that Rab25 functions as a tumour suppressor or oncogene depending on the cancer type [10][11][12] . In addition, loss of Rab21 correlates with increased malignancy in prostate and ovarian cancer 13 .…”

Downregulation of Rab25 activates Akt1 in head and neck squamous cell carcinoma

“…Increased expression of Rab25 was observed in breast, ovarian and bladder cancer, and was associated with aggressive tumor features (22,23,28). By contrast, a tumor suppressor role for Rab25 has also been demonstrated in colon cancer, triple-negative breast cancer and esophageal SCC (ESCC) (31,37,38). These results indicate that changes in the expression of Rab25 may depend on the cell type and, therefore, the mechanism underlying the effect of this protein on cancer progression may be tumor-type specific.…”