Secretory RAB GTPase 3C modulates IL6-STAT3 pathway to promote colon cancer metastasis and is associated with poor prognosis

Molecular Cancer

Research

Ming-Huang Chen¹  Chi-Long Chen²  Wei-Shone Chen³  Chia-Yi Su⁴  Michael Hsiao⁵  Yu-Chan Chang⁶ 

[1] Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan;School of Medicine, National Yang-Ming University, 112, Taipei, Taiwan;Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan;Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan;Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan;Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan;Genomics Research Center, Academia Sinica, Taipei, Taiwan;Genomics Research Center, Academia Sinica, Taipei, Taiwan;Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan;Genomics Research Center, Academia Sinica, Taipei, Taiwan;

关键词: RAB GTPases;    RAB3C;    IL-6;    STAT3;    Colon cancer;   

DOI  :  10.1186/s12943-017-0687-7

 received in 2016-08-29, accepted in 2017-06-26,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundRAB GTPases are important in the regulation of membrane trafficking and cell movement. Recently, exocytic RABs have received increasing attention in cancer research. However, the functional roles of exocytic RABs in colorectal carcinogenesis remain to be elucidated.MethodsImmunohistochemistry analysis of a microarray containing 215 colorectal adenocarcinoma tissues was used to identify the association between exocytic RABs and patient prognosis. Complementary functional RAB3C overexpression and knockdown experiments were performed. The molecular mechanism of RAB3C in inducing colon cancer cell metastasis was determined.ResultsHigh RAB3C expression in patients was found to be significantly associated with advanced pathological stage, distant metastasis and poor prognosis. Multivariate analyses showed that high RAB3C expression was an independent prognostic marker in overall (P = 0.001) and disease-free survival (P < 0.001). Furthermore, our experimental results showed an increase in the migration and invasion ability of RAB3C-overexpressing colon cancer cells and increased metastatic nodules in a mouse metastasis model. The effect of RAB3C-overexpressing cell-conditioned medium was found to significantly promote the migration ability of parental colon cancer cells, thus suggesting that the promotion of migration is exocytosis dependent. Upregulation of other exocytic RABs was also seen in RAB3C-overexpressing cells. Through microarray and proteomics analyses, increased production of multiple cytokines was observed in RAB3C-overexpressing cell lines, and the IL-6 pathway was the top pathway whose members exhibited gene expression changes after RAB3C overexpression, according to Ingenuity Pathway Analysis. Blocking IL-6 with IL-6 antibody treatment or IL-6 knockdown significantly inhibited the migration potential of RAB3C-overexpressing colon cancer cells. In addition, IL-6 was found to induce STAT3 phosphorylation in RAB3C-overexpressing colon cancer cells, thus promoting migration. Ruxolitinib, a JAK2 inhibitor, was found to significantly inhibit RAB3C-induced colon cancer cell migration.ConclusionsOur study revealed that RAB3C overexpression promotes tumor metastasis and is associated with poor prognosis in colorectal cancer, through modulating the ability of cancer cells to release IL-6 through exocytosis and activate the JAK2-STAT3 signaling pathway. These results further suggest that inhibition of STAT3 phosphorylation in the RAB3C-IL-6-STAT3 axis by using Ruxolitinib may be a new therapeutic strategy to combat metastatic colon cancers.

【 授权许可】

CC BY   
© The Author(s). 2017