Journal
ONCOTARGET
Volume 7, Issue 13, Pages 16567-16580Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7767
Keywords
mesenchymal stem cells; gastric cancer; microRNA; tumor microenvironment
Categories
Funding
- National Natural Science Foundation of China [81302119, 81472334]
- Natural Science Foundation of the Jiangsu Province [BK20130540]
- Jiangsu Province for Natural Science Research in Colleges and Universities [13KJB320001]
- Jiangsu University Excellent Young Teacher Training Project
- Scientific Research Foundation of Jiangsu University for Senior Professional Talents [13JDG088]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Jiangsu Province for Outstanding Sci-tech Innovation Team in Colleges and Universities [SJK2013-10]
- Innovation Project for Graduate Student Research of Jiangsu Province [KYLX_1075]
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Gastric cancer tissue-derived MSC-like cells (GC-MSC) share similar characteristics to bone marrow MSC (BM-MSC); however, the phenotypical and functional differences and the molecular mechanism of transition between the two cell types remain unclear. Compared to BM-MSC, GC-MSC exhibited the classic phenotype of reactive stroma cells, a stronger gastric cancer promoting capacity and lower expression of miR-155-5p. Inhibition of miR-155-5p by transfecting miRNA inhibitor induced a phenotypical and functional transition of BM-MSC into GC-MSC-like cells, and the reverse experiment deprived GC-MSC of tumor-promoting phenotype and function. NF-kappa B p65 (NF-kappa B p65) and inhibitor of NF-kappa B kinase subunit epsilon (IKBKE/IKK epsilon) were identified as targets of miR-155-5p and important for miRNA inhibitor activating NF-kappa B p65 in the transition. Inactivation of NF-kappa B by pyrrolidine dithiocarbamic acid (PDTC) significantly blocked the effect of miR-155-5p inhibitor on BM-MSC. IKBKE, NF-kappa B p65 and phospho-NF-kappa B p65 proteins were highly enriched in MSC-like cells of gastric cancer tissues, and the latter two were correlated with the pathological progression of gastric cancer. In GC-MSC, the expression of miR-155-5p was downregulated and NF-kappa B p65 protein was increased and activated. NF-kappa B inactivation by PDTC or knockdown of its downstream cytokines reversed the phenotype and function of GC-MSC. Taken together, our findings revealed that miR-155-5p downregulation induces BM-MSC to acquire a GC-MSC-like phenotype and function depending on NF-kappa B p65 activation, which suggests a novel mechanism underlying the cancer associated MSC remodeling in the tumor microenvironment and offers an effective target and approach for gastric cancer therapy.
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