Abstract 5813: Rab GTPase 3C promotes colon cancer metastasis via regulation of IL-6 secretion and STAT3 signaling pathway

Abstract

Abstract RAB GTPases is involved in membrane trafficking vesicle formation and cell motility. Recently, exocytotic RABs received growing attention in cancer research. However, the molecular mechanism of exocytotic RABs in colorectal tumorigenicity remains unclear. In this study, we found RAB GTPase 3C (RAB3C) has the most significant association with higher pathological stage, tumor recurrence, frequent distant metastasis, and poor prognosis in 215 colorectal adenocarcinoma cohort using tissue microarray (TMA) analysis. In multivariate analyses, high RAB3C expression retained its independently prognostic significance for both overall survival (p=0.001) and disease-free survival (p < 0.001). Further experimental results showed increased migration and invasion ability in RAB3C overexpressing colon cancer cells compared with control group in vitro and in vivo. The cell culture medium collected from RAB3C overexpressing model could promote parental colon cancer cells further indicated that the metastasis-promoting role of RAB3C is exocytosis dependent. We then integrated the results from previously microarray and proteomics datasets and discovered that increased production of multiple cytokines in RAB3C overexpressing cell lines. Of these cytokines, IL-6 pathway is the top pathway corresponding to gene expression changes after RAB3C overexpression. Blocking of IL-6 function with IL-6 antibody or IL-6 knockdown significantly reduced the migration ability in RAB3C overexpressing colon cancer cells. Furthermore, secretion of IL-6 after RAB3C overexpression promoted the JAK2-STAT3 signaling with increased STAT3 phosphorylation levels to promote migration. In addition, Ruxolitinib, a JAK2 inhibitor, was found to significantly inhibited RAB3C induced colon cancer cell migration through blocking STAT3 phosphorylation. In conclusion, our study showed that RAB3C overexpression promoted tumor metastasis and is associated with poor prognosis of colon cancer patients through modulating the IL6 exocytosis of cancer cells to activate JAK2-STAT3 pathway. These findings suggest a new therapeutic strategy through the inhibition of STAT3 signaling pathway in RAB3C-IL-6 axis by Ruxolitinib to prevent metastasis of colon cancer. Note: This abstract was not presented at the meeting. Citation Format: Chi-Long Chen. Rab GTPase 3C promotes colon cancer metastasis via regulation of IL-6 secretion and STAT3 signaling pathway [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 5813. doi:10.1158/1538-7445.AM2017-5813