Abstract 514: ARHGEF15 is associated with a poor prognosis in patients with pancreatic ductal adenocarcinoma through a mechanism involving the enhancement of cellular motility and proliferation

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and is associated with an extremely poor prognosis, since it is difficult to diagnose pancreatic cancer at an early stage despite its remarkably aggressive features. However, the molecular mechanism underlying the development of aggressive PDAC remains elusive. Rho guanine nucleotide exchange factors (ARHGEFs) are known to activate the RhoA signaling pathway in several types of tumor, although its association with the outcome of PDAC has not been reported. Here, we report that a higher expression of ARHGEF15 is significantly associated with a poor prognosis among PDAC patients, and an increase in ARHGEF15 expression plays pivotal roles in the enhancement of cellular motility and the proliferation of PDAC cells. Firstly, we found that a higher level of ARHGEF15 was significantly correlated with a poor prognosis among 39 Japanese patients with PDAC using global gene expression profiling with an Affymetrix microarray. We then showed that RNA interference-mediated gene silencing of ARHGEF15 inactivated the RhoA signaling pathway when examined using a RhoA pull-down assay. Next, the assessment of cellular migration using both a transwell chamber assay and a wound healing assay showed that ARHGEF15 silencing down-regulated cellular migration and invasive ability in pancreatic cancer cell lines with high levels of endogenous ARHGEF15 expression. Since the RhoA signaling pathway is involved in cell proliferation, we also examined the effect of ARHGEF15-silencing on cell viability and observed that ARHGEF15-knockdown markedly retarded cellular growth in the pancreatic cell lines. In parallel with the gene-silencing studies, the effect of ARHGEF15-overexpression was also investigated in pancreatic cell lines with low levels of endogenous ARHGEF15 expression. We observed opposite phenotypes to those observed in the gene-silencing studies: increased cellular motility and viability, compared with the controls, was observed as a result of overexpression. This is the first study to suggest that a higher expression of ARHGEF15 was correlated with a poor prognosis among patients with pancreatic cancer. In addition, these data suggested that the overexpression of ARHGEF15 contributed to a poor prognosis among PDAC patients by enhancing tumor motility and proliferation, suggesting that ARHGEF15 could be a prognostic biomarker as well as a novel therapeutic target for PDAC. Citation Format: Hiroto Fukushima, Makiko Yasumoto, Sachiko Ogasawara, Jun Akiba, Yuhei Kitasato, Yoshiki Naito, Masamichi Nakayama, Yoshinobu Okabe, Masafumi Yasunaga, Hiroyuki Horiuchi, Etsuko Sakamoto, Hiraku Itadani, Shinji Mizuarai, Shinji Oie, Hirohisa Yano. ARHGEF15 is associated with a poor prognosis in patients with pancreatic ductal adenocarcinoma through a mechanism involving the enhancement of cellular motility and proliferation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 514. doi:10.1158/1538-7445.AM2015-514