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.
Highlights
Esophageal cancer ranks as the sixth leading cause of cancer-related deaths worldwide, with distinctly high incidences and mortality rates in East Asia, Africa, and North America [1]
Among the differentially expressed genes involved in integrin signaling, Ras-related protein Rab25 was found to be the only significantly downregulated gene in Esophageal squamous cell carcinoma (ESCC) compared with nontumor tissue and was chosen for further studies
Collection of esophageal tissue samples All clinical specimens used for RNA-Seq and Rab25 expression studies by quantitative real-time PCR, Western blotting, and immunohistochemistry were collected from patients with ESCCs who underwent surgical resection of tumor tissues at Linzhou Cancer Hospital (Henan, China)
Summary
Esophageal cancer ranks as the sixth leading cause of cancer-related deaths worldwide, with distinctly high incidences and mortality rates in East Asia, Africa, and North America [1]. Esophageal squamous cell carcinoma (ESCC) is the most common form of esophageal cancer. The disease is characterized by regional variation in incidences. More than 50% of all ESCC cases in the world occur in China. In. Authors' Affiliations: Departments of 1Pathology and 2Clinical Oncology, 3Genome Research Centre, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; and 4Department of Clinical Oncology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Accession code: Transcriptome sequencing data have been submitted to Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) under the accession number GSE32424
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