Abstract
Introduction: Resident mesenchymal stem cells (MSCs) in the tumor microenvironment play an important role in tumor progression. Up to now, the mechanism of resident MSCs promoting gastric cancer cell migration remains unclear.
Methods: We tested the migration ability of gastric cancer cells by transwell assays in this study. The inflammatory factors secreted by MSCs were detected by Luminex and ELISA. The activation of NF-κB signaling was detected by western blot. The exosomes derived from MSCs were isolated and identified by transmission electron microscope, nano-sight and western blot. The expression of miR-374a-5p was confirmed by qRT-PCR and its downstream target HAPLN1 by luciferase reporter assay. The expression of adhesion molecules of gastric cancer cells was detected by flow cytometry.
Results: MiR-374a-5p could regulate the expression of inflammatory factors by activating NF-κB signaling. The increase of MCP-1 and the decrease of IFN-γ promoted the migration of gastric cancer cells. The miR-374a-5p in MSCs could be encapsulated and delivered to gastric cancer cells by exosomes derived from MSCs. Exogenous miR-374a-5p up-regulated the expression of adhesion molecules in gastric cancer cells by targeting HAPLN1. And miR-374a-5p-enriched exosomes also promoted the migration of gastric cancer cells.
Conclusion: MiR-374a-5p promoted gastric cancer metastasis, and resident MSCs in the gastric cancer microenvironment played a major role in the regulation of gastric cancer metastasis. The study will provide new ideas and potential targets for the prevention and treatment of gastric cancer metastasis.
Graphical Abstract
[1]
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-49.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin 2021; 71(1): 7-33.
[http://dx.doi.org/10.3322/caac.21654] [PMID: 33433946]
[http://dx.doi.org/10.3322/caac.21654] [PMID: 33433946]
[3]
Digklia A, Wagner AD. Advanced gastric cancer: Current treatment landscape and future perspectives. World J Gastroenterol 2016; 22(8): 2403-14.
[http://dx.doi.org/10.3748/wjg.v22.i8.2403] [PMID: 26937129]
[http://dx.doi.org/10.3748/wjg.v22.i8.2403] [PMID: 26937129]
[4]
Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19(11): 1423-37.
[http://dx.doi.org/10.1038/nm.3394] [PMID: 24202395]
[http://dx.doi.org/10.1038/nm.3394] [PMID: 24202395]
[5]
Li S, Cong X, Gao H, et al. Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells. J Exp Clin Cancer Res 2019; 38(1): 6.
[http://dx.doi.org/10.1186/s13046-018-1003-0] [PMID: 30616627]
[http://dx.doi.org/10.1186/s13046-018-1003-0] [PMID: 30616627]
[6]
Timaner M, Tsai KK, Shaked Y. The multifaceted role of mesenchymal stem cells in cancer. Semin Cancer Biol 2020; 60: 225-37.
[http://dx.doi.org/10.1016/j.semcancer.2019.06.003] [PMID: 31212021]
[http://dx.doi.org/10.1016/j.semcancer.2019.06.003] [PMID: 31212021]
[7]
Hass R. Role of MSC in the tumor microenvironment. Cancers (Basel) 2020; 12(8): 2107.
[http://dx.doi.org/10.3390/cancers12082107] [PMID: 32751163]
[http://dx.doi.org/10.3390/cancers12082107] [PMID: 32751163]
[8]
Cheng YQ, Wang SB, Liu JH, et al. Modifying the tumour microenvironment and reverting tumour cells: New strategies for treating malignant tumours. Cell Prolif 2020; 53(8): e12865.
[http://dx.doi.org/10.1111/cpr.12865] [PMID: 32588948]
[http://dx.doi.org/10.1111/cpr.12865] [PMID: 32588948]
[9]
Katanov C, Lerrer S, Liubomirski Y, et al. Regulation of the inflammatory profile of stromal cells in human breast cancer: Prominent roles for TNF-α and the NF-κB pathway. Stem Cell Res Ther 2015; 6(1): 87.
[http://dx.doi.org/10.1186/s13287-015-0080-7] [PMID: 25928089]
[http://dx.doi.org/10.1186/s13287-015-0080-7] [PMID: 25928089]
[10]
Che Y, Shi X, Shi Y, et al. Exosomes derived from miR-143-overexpressing MSCs inhibit cell migration and invasion in human prostate cancer by downregulating TFF3. Mol Ther Nucleic Acids 2019; 18: 232-44.
[http://dx.doi.org/10.1016/j.omtn.2019.08.010] [PMID: 31563120]
[http://dx.doi.org/10.1016/j.omtn.2019.08.010] [PMID: 31563120]
[11]
Bian H, Zhou Y, Zhou D, Zhang Y, Shang D, Qi J. The latest progress on miR‐374 and its functional implications in physiological and pathological processes. J Cell Mol Med 2019; 23(5): 3063-76.
[http://dx.doi.org/10.1111/jcmm.14219] [PMID: 30772950]
[http://dx.doi.org/10.1111/jcmm.14219] [PMID: 30772950]
[12]
Xie J, Tan ZH, Tang X, et al. miR-374b-5p suppresses RECK expression and promotes gastric cancer cell invasion and metastasis. World J Gastroenterol 2014; 20(46): 17439-47.
[http://dx.doi.org/10.3748/wjg.v20.i46.17439] [PMID: 25516656]
[http://dx.doi.org/10.3748/wjg.v20.i46.17439] [PMID: 25516656]
[13]
Xu X, Wang W, Su N, et al. miR-374a promotes cell proliferation, migration and invasion by targeting SRCIN1 in gastric cancer. FEBS Lett 2015; 589(3): 407-13.
[http://dx.doi.org/10.1016/j.febslet.2014.12.027] [PMID: 25554419]
[http://dx.doi.org/10.1016/j.febslet.2014.12.027] [PMID: 25554419]
[14]
Long ZW, Wu JH. Cai-Hong, Wang YN, Zhou Y. MiR-374b promotes proliferation and inhibits apoptosis of human GIST cells by inhibiting PTEN through activation of the PI3K/Akt pathway. Mol Cells 2018; 41(6): 532-44.
[PMID: 29902839]
[PMID: 29902839]
[15]
Ji R, Zhang X, Gu H, et al. miR-374a-5p: A new target for diagnosis and drug resistance therapy in gastric cancer. Mol Ther Nucleic Acids 2019; 18: 320-31.
[http://dx.doi.org/10.1016/j.omtn.2019.07.025] [PMID: 31614322]
[http://dx.doi.org/10.1016/j.omtn.2019.07.025] [PMID: 31614322]
[16]
Sun Z, Chen J, Zhang J, et al. The role and mechanism of miR-374 regulating the malignant transformation of mesenchymal stem cells. Am J Transl Res 2018; 10(10): 3224-32.
[PMID: 30416663]
[PMID: 30416663]
[17]
Ji R, Zhang X, Qian H, et al. miR-374 mediates the malignant transformation of gastric cancer-associated mesenchymal stem cells in an experimental rat model. Oncol Rep 2017; 38(3): 1473-81.
[http://dx.doi.org/10.3892/or.2017.5831] [PMID: 28731132]
[http://dx.doi.org/10.3892/or.2017.5831] [PMID: 28731132]
[18]
Hughes RM, Simons BW, Khan H, et al. Asporin restricts mesenchymal stromal cell differentiation, alters the tumor microenvironment, and drives metastatic progression. Cancer Res 2019; 79(14): 3636-50.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-2931] [PMID: 31123087]
[http://dx.doi.org/10.1158/0008-5472.CAN-18-2931] [PMID: 31123087]
[19]
Melzer C, von der Ohe J, Hass R. Enhanced metastatic capacity of breast cancer cells after interaction and hybrid formation with mesenchymal stroma/stem cells (MSC). Cell Commun Signal 2018; 16(1): 2.
[http://dx.doi.org/10.1186/s12964-018-0215-4] [PMID: 29329589]
[http://dx.doi.org/10.1186/s12964-018-0215-4] [PMID: 29329589]
[20]
Melzer C, Yang Y, Hass R. Interaction of MSC with tumor cells. Cell Commun Signal 2016; 14(1): 20.
[http://dx.doi.org/10.1186/s12964-016-0143-0] [PMID: 27608835]
[http://dx.doi.org/10.1186/s12964-016-0143-0] [PMID: 27608835]
[21]
Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007; 449(7162): 557-63.
[http://dx.doi.org/10.1038/nature06188] [PMID: 17914389]
[http://dx.doi.org/10.1038/nature06188] [PMID: 17914389]
[22]
Li W, Zhou Y, Yang J, et al. Gastric cancer-derived mesenchymal stem cells prompt gastric cancer progression through secretion of interleukin-8. J Exp Clin Cancer Res 2015; 34(1): 52.
[http://dx.doi.org/10.1186/s13046-015-0172-3] [PMID: 25986392]
[http://dx.doi.org/10.1186/s13046-015-0172-3] [PMID: 25986392]
[23]
Sun C, Li X, Guo E, et al. MCP-1/CCR-2 axis in adipocytes and cancer cell respectively facilitates ovarian cancer peritoneal metastasis. Oncogene 2020; 39(8): 1681-95.
[http://dx.doi.org/10.1038/s41388-019-1090-1] [PMID: 31705064]
[http://dx.doi.org/10.1038/s41388-019-1090-1] [PMID: 31705064]
[24]
Zhan Z, Xie X, Cao H, et al. Autophagy facilitates TLR4- and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination. Autophagy 2014; 10(2): 257-68.
[http://dx.doi.org/10.4161/auto.27162] [PMID: 24321786]
[http://dx.doi.org/10.4161/auto.27162] [PMID: 24321786]
[25]
Wu Y, Liu J, Movahedi F, Gu W, Xu T, Xu ZP. Enhanced prevention of breast tumor metastasis by nanoparticle-delivered vitamin E in combination with interferon-gamma. Adv Healthc Mater 2020; 9(6): 1901706.
[http://dx.doi.org/10.1002/adhm.201901706] [PMID: 32052565]
[http://dx.doi.org/10.1002/adhm.201901706] [PMID: 32052565]
[26]
Gkouveris I, Nikitakis N, Asservatham J, Ogbureke K. Interferon γ suppresses dentin sialophosphoprotein in oral squamous cell carcinoma cells resulting in antitumor effects, via modulation of the endoplasmic reticulum response. Int J Oncol 2018; 53(6): 2423-32.
[http://dx.doi.org/10.3892/ijo.2018.4590] [PMID: 30320380]
[http://dx.doi.org/10.3892/ijo.2018.4590] [PMID: 30320380]
[27]
Cioni B, Nevedomskaya E, Melis MHM, et al. Loss of androgen receptor signaling in prostate cancer‐associated fibroblasts (CAFs) promotes CCL2‐ and CXCL8‐mediated cancer cell migration. Mol Oncol 2018; 12(8): 1308-23.
[http://dx.doi.org/10.1002/1878-0261.12327] [PMID: 29808619]
[http://dx.doi.org/10.1002/1878-0261.12327] [PMID: 29808619]
[28]
Baci D, Bruno A, Cascini C, et al. Acetyl-L-Carnitine downregulates invasion (CXCR4/CXCL12, MMP-9) and angiogenesis (VEGF, CXCL8) pathways in prostate cancer cells: Rationale for prevention and interception strategies. J Exp Clin Cancer Res 2019; 38(1): 464.
[http://dx.doi.org/10.1186/s13046-019-1461-z] [PMID: 31718684]
[http://dx.doi.org/10.1186/s13046-019-1461-z] [PMID: 31718684]
[29]
Wang X, Luo G, Zhang K, et al. Hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis. Cancer Res 2018; 78(16): 4586-98.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-3841] [PMID: 29880482]
[http://dx.doi.org/10.1158/0008-5472.CAN-17-3841] [PMID: 29880482]
[30]
Fang JH, Zhang ZJ, Shang LR, et al. Hepatoma cell‐secreted exosomal microRNA‐103 increases vascular permeability and promotes metastasis by targeting junction proteins. Hepatology 2018; 68(4): 1459-75.
[http://dx.doi.org/10.1002/hep.29920] [PMID: 29637568]
[http://dx.doi.org/10.1002/hep.29920] [PMID: 29637568]
[31]
Sun LP, Xu K, Cui J, et al. Cancer associated fibroblast derived exosomal miR 382 5p promotes the migration and invasion of oral squamous cell carcinoma. Oncol Rep 2019; 42(4): 1319-28.
[http://dx.doi.org/10.3892/or.2019.7255] [PMID: 31364748]
[http://dx.doi.org/10.3892/or.2019.7255] [PMID: 31364748]
[32]
Ecker BL, Kaur A, Douglass SM, et al. Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. Cancer Discov 2019; 9(1): 82-95.
[http://dx.doi.org/10.1158/2159-8290.CD-18-0168] [PMID: 30279172]
[http://dx.doi.org/10.1158/2159-8290.CD-18-0168] [PMID: 30279172]
[33]
Tammi MI, Oikari S, Pasonen-Seppänen S, Rilla K, Auvinen P, Tammi RH. Activated hyaluronan metabolism in the tumor matrix — Causes and consequences. Matrix Biol 2019; 78-79: 147-64.
[http://dx.doi.org/10.1016/j.matbio.2018.04.012] [PMID: 29709595]
[http://dx.doi.org/10.1016/j.matbio.2018.04.012] [PMID: 29709595]
[34]
Sullivan WJ, Mullen PJ, Schmid EW, et al. Extracellular matrix remodeling regulates glucose metabolism through TXNIP destabilization. Cell 2018; 175(1): 117-132.e21.
[http://dx.doi.org/10.1016/j.cell.2018.08.017] [PMID: 30197082]
[http://dx.doi.org/10.1016/j.cell.2018.08.017] [PMID: 30197082]
[35]
Kaur A, Ecker BL, Douglass SM, et al. Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. Cancer Discov 2019; 9(1): 64-81.
[http://dx.doi.org/10.1158/2159-8290.CD-18-0193] [PMID: 30279173]
[http://dx.doi.org/10.1158/2159-8290.CD-18-0193] [PMID: 30279173]
