Integrative Genomics IdentifiesRAB23as an Invasion Mediator Gene in Diffuse-Type Gastric Cancer

Abstract

Recurrent genomic amplifications and deletions are frequently observed in primary gastric cancers (GC). However, identifying specific oncogenes and tumor suppressor genes within these regions can be challenging, as they often cover tens to hundreds of genes. Here, we combined high-resolution array-based comparative genomic hybridization (aCGH) with gene expression profiling to target genes within focal high-level amplifications in GC cell lines, and identified RAB23 as an amplified and overexpressed Chr 6p11p12 gene in Hs746T cells. High RAB23 protein expression was also observed in some lines lacking RAB23 amplification, suggesting additional mechanisms for up-regulating RAB23 besides gene amplification. siRNA silencing of RAB23 significantly reduced cellular invasion and migration in Hs746T cells, whereas overexpression of RAB23 enhanced cellular invasion in AGS cells. RAB23 amplifications in primary gastric tumors were confirmed by both fluorescence in situ hybridization and genomic qPCR, and in two independent patient cohorts from Hong Kong and the United Kingdom RAB23 expression was significantly associated with diffuse-type GC (dGC) compared with intestinal-type GC (iGC). These results provide further evidence that dGC and iGC likely represent two molecularly distinct tumor types, and show that investigating focal chromosomal amplifications by combining highresolution aCGH with expression profiling is a powerful strategy for identifying novel cancer genes in regions of recurrent chromosomal aberration. [Cancer Res 2008;68(12): 4623-30]

MicroRNA network analysis identifies key microRNAs and genes associated with precancerous lesions of gastric cancer

“…Endosomes play key roles in the control of cell signaling, the epithelial to mesenchymal transition, and cell adhesion and migration, thus influencing cancer development (Lanzetti and Di Fiore, 2008). Several studies have demonstrated that members of the RAB family are up-regulated in GC tissues (Hou et al, 2008;Cao et al, 2013). SOX4 is a member of the SRYrelated HMG-box (SOX) family of transcription factors involved in cell apoptosis as well as tumorigenesis.…”

Rabs and cancer cell motility

“…Other than the Rabs described above, other Rabs, such as Rab23, have also been linked to cancer cell migration and invasion [Hou et al, 2008]. In this case, however, the underlying mechanism is unclear.…”

The role of endocytic Rab GTPases in regulation of growth factor signaling and the migration and invasion of tumor cells

“…Rab23 is overexpressed in bladder, 73 gastric 74 and ovarian carcinoma 75 while it is purported to be downregulated in triple negative breast cancer. 76,77 Similarly Rab25 has differing expression levels with increased expression in estrogen and progesterone receptor positive breast cancer, 78 and suppression in colon and head and neck tumors.…”

“…77 However, Rab25 is also said to be an oncogene given its role in advanced stages of ovarian and breast cancers and is linked to an increase in malignancy and migration of the epithelial cells by modulating cell proliferation (both anchorage dependent and independent cells), trafficking of integrin and suppressing apoptosis. 75 Specifically, Rab25 promotes cell survival by increasing PI3-Kinase signaling through the interaction with the Rab-coupling protein, which in turn sustains the recycling of both EGFR and the fibronectin receptor (integrin a5b1). It was determined that Rab25 accelerates cell migration by actively moderating the recycling of integrins via the chloride intracellular channel protein 3 where this process is required in the freeing of the cell rear in cell migration and invasion.…”

“…130 On the other hand, Rab31 overexpression engendered a shift from a highly invasive capacity to a less invasive and highly proliferative phenotype in an experimental mouse model. 131 Rab4 has also been implicated in the secretion of procathepsin-L, another significant protease required in the modulation of the tumor microenvironment where suppression of Rab4 expression led to a reduction of tumor mass. 132 Growth-factor stimulated breast cancer cells overexpressing Rab5a affected Rab4 and Rabenosyn-5-dependent endo/exocytic cycles in the ferrying of the matrix protease, MT1-MMP and b3 integrin.…”