title: 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.
authors.affiliation: Department of Pathology, Genome Research Centre, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Man
authors.initials: M
authors.lastname: Tong
authors.forename: Kwok Wah
authors.initials: KW
authors.lastname: Chan
authors.forename: Jessie Y J
authors.initials: JY
authors.lastname: Bao
authors.forename: Kai Yau
authors.initials: KY
authors.lastname: Wong
authors.forename: Jin-Na
authors.initials: JN
authors.lastname: Chen
authors.forename: Pak Shing
authors.initials: PS
authors.lastname: Kwan
authors.forename: Kwan Ho
authors.initials: KH
authors.lastname: Tang
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.forename: Yan-Ru
authors.initials: YR
authors.lastname: Qin
authors.forename: Si
authors.initials: S
authors.lastname: Lok
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ma
mesh_terms: D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C509763:Rab25 protein, human; D020691:rab GTP-Binding Proteins