Abstract 4340: RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk

Abstract

Abstract Background: Cancer-associated fibroblasts (CAFs) have been reported to promote various types of tumor through secretion of soluble factors. However, there have been no systematic studies of CAFs in diffuse-type gastric cancers (DGCs). We investigated the characteristics and functional roles of CAFs in DGCs using comprehensive genomic approach. Methods: We established primary fibroblasts, normal fibroblasts (NFs) and CAFs from more than 100 tissue samples from GC patients. NFs/CAFs were subjected to Exome and RNA sequencing, and the possible candidates for functional assay were selected from among the acquired comprehensive data. The candidate molecules were examined the functional roles for GC tumor progression by in vitro assays. Results: CAFs exhibited an invasive molecular pattern and acquired motility in extracellular matrix (ECM). We identified RHBDF2 as a mediator of TGF-β signaling and an enhancer of CAF motility. RHBDF2 silencing in CAFs significantly decreased their motility stimulated by TGF-β1 in ECM, whereas NFs transfected with the RHBDF2 expression vector displayed a greater motility in ECM than did control NFs. RHBDF2 silencing also decreased type I TGF-β receptor (TβRI) cleavage through tumor necrosis factor (TNF)-α converting enzyme (TACE) activity and attenuated the invasive molecular pattern of CAFs. Consequently, high-motility CAFs confer on DGC cells the ability to invade the ECM. Furthermore, simultaneous treatment with interleukin (IL)-1α, IL-1β and TNF-α resulted in a strong induction of RHBDF2 expression in NFs. The expression of these cytokines in GC tissues was associated with poor prognosis in GC patients. Conclusion: These findings highlight the underlying mechanism whereby DGC cells take advantage of CAFs to acquire invasiveness. Citation Format: Takatsugu Ishimoto, Keisuke Miyake, Masakazu Yashiro, Tsugio Eto, Daisuke Izumi, Kota Arima, Yoshifumi Baba, Masayuki Watanabe, Kosei Hirakawa, Hideo Baba, Patrick Tan. RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4340. doi:10.1158/1538-7445.AM2017-4340