Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases, associated with a remarkably poor prognosis. However, the molecular mechanisms underlying the development of PDAC remain elusive. The aim of this study was to identify genes whose expressions are correlated with a poor prognosis in PDAC patients, and to unravel the mechanisms underlying the involvement of these genes in the development of the cancer.MethodsGlobal gene expression profiling was conducted in 39 specimens obtained from Japanese patients with PDAC to identify genes whose expressions were correlated with a shorter overall survival. The effect of gene silencing or overexpression of ARHGEF15 in pancreatic cancer cell lines was examined by introducing siRNAs of ARHGEF15 or the ARHGEF15 expression vector. After assessing the effect of ARHGEF15 deregulation on the Rho-family proteins by pull-down assay, wound healing, transwell and cell viability assays were carried out to investigate the cellular phenotypes caused by the perturbation.ResultsThe global mRNA expression profiling revealed that overexpression of ARHGEF15, a Rho-specific GEF, was significantly associated with a poor prognosis in patients with PDAC. We also found that the depletion of ARHGEF15 by RNA interference in pancreatic cancer cell lines downregulated the activities of molecules of the Rho signaling pathway, including RhoA, Cdc42 and Rac1. Then, we also showed that ARHGEF15 silencing significantly reduced the motility and viability of the cells, while its overexpression resulted in the development of the opposite phenotype in multiple pancreatic cancer cell lines.ConclusionThese data suggest that upregulation of ARHGEF15 contributes to the development of aggressive PDAC by increasing the growth and motility of the pancreatic cancer cells, thereby worsening the prognosis of these patients. Therefore, ARHGEF15 could serve as a novel therapeutic target in patients with PDAC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0516-4) contains supplementary material, which is available to authorized users.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases, associated with a remarkably poor prognosis
The ARHGEF15 expression level was elevated in the tumor tissues of PDAC patients with a poor Prognosis To identify the molecular mechanism underlying the exceptionally poor prognosis of PDAC, we performed a global gene expression analysis using the Affymetrix X3P GeneChip microarray, and carried out an analysis of the prognosis in relation to the tumor gene expression profiles of the 39 PDAC patients enrolled in the study
The samples were divided into two groups: the poor prognosis group, in which the overall survival (OS) was shorter than the median OS, and the better prognosis group, in which the OS was longer than the median OS
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases, associated with a remarkably poor prognosis. VAV guanine nucleotide exchange factor 1 (VAV1) is reported to be overexpressed in clinical pancreatic carcinoma cells, leading to activation of Rac signaling, resulting in decreased survival in pancreatic cancer patients [12, 13]. VAV guanine nucleotide exchange factor 2 (VAV2) is hyperactivated in head and neck squamous cell carcinoma, and its molecular role was assessed by VAV2silencing; this investigation revealed that inactivated Rac signaling leads to a decreased invasiveness of cancers [14] Another example signifying the crucial roles of GEFs in cancer development is the identification of the chromosomal rearrangement in acute myelogenous leukemia (AML) that results in the generation of the fusion protein MLL-ARHGEF12 [15]. These reports suggest the potentially significant roles of RhoGEFs in tumorigenesis
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