低氧预处理人胎盘绒毛膜间充质干细胞环状RNAs的生物信息学分析
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摘要
目的采用生物信息学方法预测低氧预处理人胎盘绒毛膜间充质干细胞环状RNAs相对应的miRNA及其靶基因,并分析靶基因所参与的生物学过程和信号通路。方法用Arraystar公司的商业软件为环状RNAs预测其相对应的miRNAs,分别用targetScan7.1和mirdbV5数据库预测miRNAs的靶基因,并取两个预测结果的合集,应用在线网站http://www.geneontology.org和http://www.genome.ad.jp/kegg对靶基因进行功能富集分析和信号通路富集分析。结果功能富集分析表明,circRNAs的靶基因主要涉及到细胞发育、细胞分化和细胞发育调控。东京基因和基因组百科全书信号通路富集分析表明肿瘤中转录失控和有丝分裂原激活蛋白激酶(MAPK)信号通路最有意义,而且分析发现MAPK信号通路为核心通路。本研究表明,低氧预处理使得间充质干细胞中部分circRNAs的表达量发生差异性变化。结论低氧预处理人胎盘绒毛膜间充质干细胞环状RNAs同低氧预处理间充质干细胞的生物学特性变化密切有关,为了解低氧预处理影响间充质干细胞特性发生变化的分子机制提供新思路。
Objective To predict the miRNA and its target genes of circular RNAs in hypoxia-preconditioned human palcenta chorionic mesenchymal stem cells using bioinformatics, and analyze the biological process and signaling pathway. Methods Arraystar's commercial software was used to predict the corresponding miRNAs of circular RNAs. The target genes of miRNAs were predicted by targetScan7.1 and mirdbV5 databases respectively, and an intersection of two prediction results was obtained. The online databases http://www. geneontology.org and http://www.genome.ad.jp/kegg performed functional enrichment analysis and signal pathway enrichment analysis of target genes. Results Functional enrichment analysis indicated that the target genes of circRNAs mainly involved cell development, cell differentiation and cell development regulation. The signal enrichment analysis of the Tokyo Gene and Genome Encyclopedia indicates that transcriptional misregulation in cancer and mitogen-activated protein kinase(MAPK) signaling pathway are most meaningful, and the MAPK signaling pathway is found to be the core pathway. This study showed that hypoxic preconditioning caused significant changes in the expression of mesenchymal stem cell circRNAs. Conclusion The changes of circular RNAs in hypoxia-preconditioned human placental chorionic mesenchymal stem cell is closely related to the biological characteristics of hypoxia-preconditioned mesenchymal stem cells. This study provides a new idea for understanding the molecular mechanism of hypoxic preconditioning affecting the changes of biological characteristics in mesenchymal stem cells.
Objective To predict the miRNA and its target genes of circular RNAs in hypoxia-preconditioned human palcenta chorionic mesenchymal stem cells using bioinformatics, and analyze the biological process and signaling pathway. Methods Arraystar's commercial software was used to predict the corresponding miRNAs of circular RNAs. The target genes of miRNAs were predicted by targetScan7.1 and mirdbV5 databases respectively, and an intersection of two prediction results was obtained. The online databases http://www. geneontology.org and http://www.genome.ad.jp/kegg performed functional enrichment analysis and signal pathway enrichment analysis of target genes. Results Functional enrichment analysis indicated that the target genes of circRNAs mainly involved cell development, cell differentiation and cell development regulation. The signal enrichment analysis of the Tokyo Gene and Genome Encyclopedia indicates that transcriptional misregulation in cancer and mitogen-activated protein kinase(MAPK) signaling pathway are most meaningful, and the MAPK signaling pathway is found to be the core pathway. This study showed that hypoxic preconditioning caused significant changes in the expression of mesenchymal stem cell circRNAs. Conclusion The changes of circular RNAs in hypoxia-preconditioned human placental chorionic mesenchymal stem cell is closely related to the biological characteristics of hypoxia-preconditioned mesenchymal stem cells. This study provides a new idea for understanding the molecular mechanism of hypoxic preconditioning affecting the changes of biological characteristics in mesenchymal stem cells.
引文
[1] MO M, WANG S, ZHOU Y, et al. Mesenchymal stem cell subpopulations: phenotype, property and therapeutic potential [J]. Cell Mol Life Sci, 2016,73(17):3311-3321.
[2] MOHAMMADIAN M, ABASI E, AKBARZADEH A. Mesenchymal stem cell-based gene therapy: a promising therapeutic strategy [J]. Artif Cells Nanomed Biotechnol, 2016,44(5):1206-1211.
[3] PELEKANOS R A, SARDESAI V S, FUTREGA K, et al. Isolation and expansion of mesenchymal stem/stromal cells derived from human placenta tissue [J]. J Vis Exp, 2016, 112:54204.
[4] PASSIPIERI J A, KASAI-BRUNSWICK T H, SUHETT G, et al. Improvement of cardiac function by placenta-derived mesenchymal stem cells does not require permanent engraftment and is independent of the insulin signaling pathway [J]. Stem Cell Res Ther, 2014,5(4):102.
[5] KIM M J, SHIN K S, JEON J H, et al. Human chorionic-plate-derived mesenchymal stem cells and Wharton's jelly-derived mesenchymal stem cells: a comparative analysis of their potential as placenta-derived stem cells [J]. Cell Tissue Res, 2011, 346(1):53- 64.
[6] LI L, JAISWAL P K, MAKHOUL G, et al. Hypoxia modulates cell migration and proliferation in placenta-derived mesenchymal stem cells [J]. J Thorac Cardiovasc Surg, 2017, 154(2):543-552.
[7] EJTEHADIFAR M, SHAMSASENJAN K, MOVASSAGHPOUR A, et al. The effect of hypoxia on mesenchymal stem cell biology [J]. Adv Pharm Bull, 2015,5(2):141-149.
[8] 孙逊沙,吴洁莹,陈劲松,等. 低氧预处理人胎盘绒毛膜间充质干细胞环状RNA筛选 [J]. 中国医药导报,2018,15(18):9-11.
[9] PASQUINELLI A E. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship [J]. Nat Rev Genet, 2012,13(4):271-282.
[10] MUZ B, de LA PUENTE P, AZAB F, AZAB A K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy [J]. Hypoxia (Auckl), 2015,3:83-92.
[11] SEMENZA G L. Hypoxia-inducible factor 1: master regulator of O2 homeostasis [J]. Curr Opin Genet Dev, 1998,8(5):588-594.
[12] HAQUE N, RAHMAN M T, ABU KASIM N H, et al. Hypoxic culture conditions as a solution for mesenchymal stem cell based regenerative therapy [J]. Sci World J, 2013,2013:632972.
[13] BURAVKOVA L B, ANDREEVA E R, GOGVADZE V, et al. Mesenchymal stem cells and hypoxia: where are we? [J]. Mitochondrion, 2014,19(Pt)A:105-112.
[14] YANG C, WU D, GAO L, et al. Competing endogenous RNA networks in human cancer: hypothesis, validation, and perspectives [J]. Oncotarget, 2016,7(12):13479-13490.
[15] HAN C, SEEBACHER N A, HORNICEK F J, et al. Regulation of microRNAs function by circular RNAs in human cancer [J]. Oncotarget, 2017,8(38):64622- 64637.
[16] LI X, PENG B, ZHU X, et al. Changes in related circular RNAs following ERβ knockdown and the relationship to rBMSC osteogenesis [J]. Biochem Biophys Res Commun, 2017,493(1): 100-107.
[17] ZHANG M, JIA L, ZHENG Y. circRNA Expression profiles in human bone marrow stem cells undergoing osteoblast differentiation [J]. Stem Cell Rev, 2018, (Epub ahead of print).
[18] CLARK E A, KALOMOIRIS S, NOLTA JA, et al. Concise review: MicroRNA function in multipotent mesenchymal stromal cells [J]. Stem Cells, 2014,32(5):1074-1082.
[19] HAMAM D, ALI D, KASSEM M, et al. microRNAs as regulators of adipogenic differentiation of mesenchymal stem cells [J]. Stem Cells Dev, 2015,24(4):417- 425.
[20] SEKAR D, SARAVANAN S, KARIKALAN K, et al. Role of microRNA 21 in mesenchymal stem cell (MSC) differentiation: a powerful biomarker in MSCs derived cells [J]. Curr Pharm Biotechnol, 2015,16(1):43- 48.
[21] KANG H, HATA A. The role of microRNAs in cell fate determination of mesenchymal stem cells: balancing adipogenesis and osteogenesis [J]. BMB Rep, 2015,48(6):319-323.
[22] YUAN Z, LI Q, LUO S, et al. PPARγ and Wnt signaling in adipogenic and osteogenic differentiation of mesenchymal stem cells [J]. Curr Stem Cell Res Ther, 2016,11(3):216-25.
[23] FANG S, DENG Y, GU P, et al. MicroRNAs regulate bone development and regeneration [J]. Int J Mol Sci, 2015,16(4):8227-8253.
[24] MAJIDINIA M, SADEGHPOUR A, YOUSEFI B. The roles of signaling pathways in bone repair and regeneration [J]. J Cell Physiol, 2018,233(4):2937-2948.
[25] MEI Y, BIAN C, LI J, et al. MiR-21 modulates the ERK-MAPK signaling pathway by regulating SPRY2 expression during human mesenchymal stem cell differentiation [J]. J Cell Biochem, 2013,114(6):1374-1384.
[26] JADLOWIEC J, KOCH H, ZHANG X, et al. Phosphophoryn regulates the gene expression and differentiation of NIH3T3, MC3T3-E1, and human mesenchymal stem cells via the integrin/MAPK signaling pathway [J]. J Biol Chem, 2004,279(51):53323-53330.
[27] JAISWAL R K, JAISWAL N, BRUDER S P, et al. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase [J]. J Biol Chem, 2000,275(13): 9645-9652.
[2] MOHAMMADIAN M, ABASI E, AKBARZADEH A. Mesenchymal stem cell-based gene therapy: a promising therapeutic strategy [J]. Artif Cells Nanomed Biotechnol, 2016,44(5):1206-1211.
[3] PELEKANOS R A, SARDESAI V S, FUTREGA K, et al. Isolation and expansion of mesenchymal stem/stromal cells derived from human placenta tissue [J]. J Vis Exp, 2016, 112:54204.
[4] PASSIPIERI J A, KASAI-BRUNSWICK T H, SUHETT G, et al. Improvement of cardiac function by placenta-derived mesenchymal stem cells does not require permanent engraftment and is independent of the insulin signaling pathway [J]. Stem Cell Res Ther, 2014,5(4):102.
[5] KIM M J, SHIN K S, JEON J H, et al. Human chorionic-plate-derived mesenchymal stem cells and Wharton's jelly-derived mesenchymal stem cells: a comparative analysis of their potential as placenta-derived stem cells [J]. Cell Tissue Res, 2011, 346(1):53- 64.
[6] LI L, JAISWAL P K, MAKHOUL G, et al. Hypoxia modulates cell migration and proliferation in placenta-derived mesenchymal stem cells [J]. J Thorac Cardiovasc Surg, 2017, 154(2):543-552.
[7] EJTEHADIFAR M, SHAMSASENJAN K, MOVASSAGHPOUR A, et al. The effect of hypoxia on mesenchymal stem cell biology [J]. Adv Pharm Bull, 2015,5(2):141-149.
[8] 孙逊沙,吴洁莹,陈劲松,等. 低氧预处理人胎盘绒毛膜间充质干细胞环状RNA筛选 [J]. 中国医药导报,2018,15(18):9-11.
[9] PASQUINELLI A E. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship [J]. Nat Rev Genet, 2012,13(4):271-282.
[10] MUZ B, de LA PUENTE P, AZAB F, AZAB A K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy [J]. Hypoxia (Auckl), 2015,3:83-92.
[11] SEMENZA G L. Hypoxia-inducible factor 1: master regulator of O2 homeostasis [J]. Curr Opin Genet Dev, 1998,8(5):588-594.
[12] HAQUE N, RAHMAN M T, ABU KASIM N H, et al. Hypoxic culture conditions as a solution for mesenchymal stem cell based regenerative therapy [J]. Sci World J, 2013,2013:632972.
[13] BURAVKOVA L B, ANDREEVA E R, GOGVADZE V, et al. Mesenchymal stem cells and hypoxia: where are we? [J]. Mitochondrion, 2014,19(Pt)A:105-112.
[14] YANG C, WU D, GAO L, et al. Competing endogenous RNA networks in human cancer: hypothesis, validation, and perspectives [J]. Oncotarget, 2016,7(12):13479-13490.
[15] HAN C, SEEBACHER N A, HORNICEK F J, et al. Regulation of microRNAs function by circular RNAs in human cancer [J]. Oncotarget, 2017,8(38):64622- 64637.
[16] LI X, PENG B, ZHU X, et al. Changes in related circular RNAs following ERβ knockdown and the relationship to rBMSC osteogenesis [J]. Biochem Biophys Res Commun, 2017,493(1): 100-107.
[17] ZHANG M, JIA L, ZHENG Y. circRNA Expression profiles in human bone marrow stem cells undergoing osteoblast differentiation [J]. Stem Cell Rev, 2018, (Epub ahead of print).
[18] CLARK E A, KALOMOIRIS S, NOLTA JA, et al. Concise review: MicroRNA function in multipotent mesenchymal stromal cells [J]. Stem Cells, 2014,32(5):1074-1082.
[19] HAMAM D, ALI D, KASSEM M, et al. microRNAs as regulators of adipogenic differentiation of mesenchymal stem cells [J]. Stem Cells Dev, 2015,24(4):417- 425.
[20] SEKAR D, SARAVANAN S, KARIKALAN K, et al. Role of microRNA 21 in mesenchymal stem cell (MSC) differentiation: a powerful biomarker in MSCs derived cells [J]. Curr Pharm Biotechnol, 2015,16(1):43- 48.
[21] KANG H, HATA A. The role of microRNAs in cell fate determination of mesenchymal stem cells: balancing adipogenesis and osteogenesis [J]. BMB Rep, 2015,48(6):319-323.
[22] YUAN Z, LI Q, LUO S, et al. PPARγ and Wnt signaling in adipogenic and osteogenic differentiation of mesenchymal stem cells [J]. Curr Stem Cell Res Ther, 2016,11(3):216-25.
[23] FANG S, DENG Y, GU P, et al. MicroRNAs regulate bone development and regeneration [J]. Int J Mol Sci, 2015,16(4):8227-8253.
[24] MAJIDINIA M, SADEGHPOUR A, YOUSEFI B. The roles of signaling pathways in bone repair and regeneration [J]. J Cell Physiol, 2018,233(4):2937-2948.
[25] MEI Y, BIAN C, LI J, et al. MiR-21 modulates the ERK-MAPK signaling pathway by regulating SPRY2 expression during human mesenchymal stem cell differentiation [J]. J Cell Biochem, 2013,114(6):1374-1384.
[26] JADLOWIEC J, KOCH H, ZHANG X, et al. Phosphophoryn regulates the gene expression and differentiation of NIH3T3, MC3T3-E1, and human mesenchymal stem cells via the integrin/MAPK signaling pathway [J]. J Biol Chem, 2004,279(51):53323-53330.
[27] JAISWAL R K, JAISWAL N, BRUDER S P, et al. Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase [J]. J Biol Chem, 2000,275(13): 9645-9652.