Journal
CANCER MEDICINE
Volume 7, Issue 3, Pages 856-868Publisher
WILEY
DOI: 10.1002/cam4.1355
Keywords
Bone marrow-derived mesenchymal stem cells; Gastric cancer; miR-155-5p; NF-B p65; tumor microenvironment
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Funding
- National Natural Science Foundation of China [81772641, 81302119, 81472334]
- China Postdoctoral Science Foundation [2017M611740]
- Jiangsu Province Postdoctoral Research Funding Scheme [1701027A]
- Young Backbone Teacher Training Project of Jiangsu University
- Jiangsu Province's Project of Key Research and Development Plan (Social Development) [BE2017694]
- Scientific Research Foundation of Jiangsu University for Senior Professional Talents [13JDG088]
- Nanjing Science and Technology Commission [201605005]
- Jiangsu Provincial Health and Family Planning Commission [LGY 2016026]
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Bone marrow-derived mesenchymal stem cells (BM-MSCs) are important precursors of tumor stromal cells. Previously, we have demonstrated that miR-155-5p inhibition directly induced transition of BM-MSCs into gastric cancer-associated MSCs. Whether miR-155-5p is involved in the education of BM-MSCs by gastric cancer cells has not been established. Murine BM-MSCs (mMSCs) were isolated and grown in conditioned medium derived from gastric cancer cell line MFC (MFC-CM). The tumor-promoting phenotype and function of mMSCs were detected by immunofluorescence staining, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), cell colony formation assay, transwell migration, and invasion assays. Luciferase reporter assays and western blot analyses were conducted to reveal the relationship between nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) p65 and mmu-miR-155-5p. miRNA mimics, inhibitor, and the NF-B inhibitor pyrrolidine dithiocarbamic acid (PDTC) were used to evaluate the role of miR-155-5p-NF-B signaling in the education of mMSCs by MFC-CM. We successfully established the education model of mMSCs by MFC-CM and found that mmu-miR-155-5p expression levels were reduced in mMSCs. Mimicking this deregulation by transfecting miRNA inhibitor into mMSCs produced a similar effect as that of MFC-CM on mMSCs. NF-B p65 was validated as a target of mmu-miR-155-5p, which also negatively regulated NF-B activation. Inhibition of NF-B activation by PDTC abolished the effect of the miRNA inhibitor on mMSCs. mmu-miR-155-5p overexpression partially blocked the effect of MFC-CM in educating mMSCs, while PDTC treatment completely eliminated MFC-CM activity. These results indicate that miR-155-5p is not the sole miRNA mediating the education of BM-MSCs by gastric cancer cells, but downstream NF-B signaling is indispensable for this process.
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