CircRNA_104293 targets miR-497-5p to inhibit the mTOR/STAT3 pathway and mitigate inflammation in Crohn’s disease.
CircRNA_104293 actúa sobre el miR-497-5p para inhibir la vía mTOR/STAT3 y mitigar la inflamación en la enfermedad de Crohn.
Resumen
La enfermedad de Crohn (CD) es una enfermedad inflamatoria crónica del intestino cuya progresión está parcialmente mediada por la disfun- ción de la vía de señalización mTOR/STAT3, en la que mTOR activa a STAT3 a través de la cascada PI3K/AKT. Recientemente, los ARN circulares (circR- NAs) han surgido como reguladores clave en procesos inflamatorios, aunque sus funciones específicas en la CD aún no están bien definidas. En este estu- dio se analizaron los perfiles de expresión de circRNAs en pacientes con CD y en controles sanos, y se identificó una sobreexpresión significativa de circR- NA_104293 en tejidos de pacientes con CD. Los análisis funcionales mostraron que la reducción de la expresión de circRNA_104293 disminuyó la producción de citocinas inflamatorias y de marcadores de daño al ADN, así como la apopto- sis celular. Mediante análisis bioinformático y validación experimental, se con- firmó una interacción directa entre circRNA_104293 y miR-497-5p. Además, la inhibición de miR-497-5p revirtió los efectos antiinflamatorios inducidos por el silenciamiento de circRNA_104293. De manera destacada, tanto la rapami- cina (un inhibidor de mTOR) como los miméticos de miR-497-5p suprimieron la activación de la vía mTOR/STAT3 y redujeron las respuestas inflamatorias. Estos hallazgos indican que el eje circRNA_104293/miR-497-5p participa en la progresión de la CD mediante la modulación de la vía mTOR/STAT3, lo que resalta su potencial como nuevo objetivo terapéutico para el tratamiento de la enfermedad de Crohn.
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Long SH, He Y, Chen MH, Cao K, Chen YJ, Chen BL, et al. Activation of PI3K/ Akt/mTOR signaling pathway triggered by PTEN downregulation in the pathogenesis of Crohn’s disease. J Dig Dis. 2013; 14(12): 662-669. https://doi.org/10.1111/1751-2980.12095.
Li L, Wan G, Han B, Zhang Z. Echinacoside alleviated LPS-induced cell apoptosis and inflammation in rat intestine epithelial cells by inhibiting the mTOR/STAT3 pathway. Biomed Pharmacother. 2018; 104: 622-628. https://doi.org/10.1016/j.biopha.2018.05.072.
Li F, Yin YK, Zhang JT, Gong HP, Hao XD. Role of circular RNAs in retinoblastoma. Funct Integr Genomics. 2022; 23(1): 13. https://doi.org/10.1007/s10142-022-00942-9.
Li L, Zhang Q and Lian K. Circular RNA circ_0000284 plays an oncogenic role in the progression of non-small cell lung cancer through the miR-377-3p-mediated PD-L1 promotion. Cancer Cell Int. 2020; 20: 247. https://doi.org/10.1186/s12935-020-01310-y.
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Zhang Y, Li C, Liu X, Wang Y, Zhao R, Yang Y, et al. circHIPK3 promotes oxaliplatin-resistance in colorectal cancer through autophagy by sponging miR-637. EBio- Medicine. 2019; 48: 277-288. https://doi.org/10.1016/j.ebiom.2019.09.051.
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Syed NH, Mussa A, Elmi AH, Jamal Al-Khreisat M, Ahmad Mohd Zain MR, Nurul AA. Role of MicroRNAs in Inflammatory Joint Diseases: A Review. Immunol Invest. 2024; 53(2): 185-209. https://doi.org/10.1080/08820139.2023.2293095.
Ke J, Chen M, Ma S, Zhang L, Zhang L. Circular R-NA VMA21 ameliorates lung injury in septic rat via targeting microRNA-497-5p/CD2-associated protein axis. Bioengineered. 2022; 13(3): 5453-5466. https://doi.org/10.1080/21655979.2022.2031406.
Lou W, Yan J, Wang W. Downregulation of miR-497-5p Improves Sepsis-Induced Acute Lung Injury by Targeting IL2RB. Biomed Res Int. 2021; 2021: 6624702. https://doi.org/10.1155/2021/6624702.
Zhang M, Yang D, Yu H, Li Q. MicroR-NA-497 inhibits inflammation in DSS- induced IBD model mice and lipopoly- saccharide-induced RAW264.7 cells via Wnt/β-catenin pathway. Int Immunopharmacol. 2021; 101(Pt B): 108318. https://doi.org/10.1016/j.intimp.2021.108318.
Ma YS, Cao YF, Liu JB, Li W, Deng J, Yang XL, et al. The power and the promise of circRNAs for cancer precision medicine with functional diagnostics and prognostic prediction. Carcinogenesis. 2021; 42(11):1305-1313. https://doi.org/10.1093/carcin/bgab071.
Yin J, Hu T, Xu L, Li P, Li M, Ye Y, et al. Circular RNA expression profile in peripheral blood mononuclear cells from Crohn disease patients. Medicine (Baltimore). 2019; 98(26): e16072. https://doi.org/10.1097/md.0000000000016072.
Lu JW, Rouzigu A, Teng LH, Liu WL. The Construction and Comprehensive Analysis of Inflammation-Related ceRNA Networks and Tissue-Infiltrating Immune Cells in Ulcerative Progression. Biomed Res Int. 2021; 2021: 6633442. https://doi.org/10.1155/2021/6633442.
Qiao YQ, Cai CW, Shen J, Zheng Q, Ran ZH. Circular RNA expression alterations in colon tissues of Crohn’s disease patients. Mol Med Rep. 2019; 19(5): 4500-4506. https://doi.org/10.3892/mmr.2019.10070.
Zhu Y, Mahon BD, Froicu M, Cantorna MT. Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Eur J Immunol. 2005; 35(1): 217-224. https://doi.org/10.1002/eji.200425491.
Sun L, Rollins D, Qi Y, Fredericks J, Mansell TJ, Jergens A, et al. TNFα regulates intestinal organoids from mice with both defined and conventional microbiota. Int J Biol Macromol. 2020; 164: 548-556. https://doi.org/10.1016/j.ijbiomac.2020.07.176.
Kaminsky LW, Al-Sadi R, Ma TY. IL -1β and the Intestinal Epithelial Tight Junction Barrier. Front Immunol. 2021; 12:767456. https://doi.org/10.3389/fimmu.2021.767456.
Van Winkle JA, Constant DA, Li L, Nice TJ. Selective Interferon Responses of Intestinal Epithelial Cells Minimize Tumor Necrosis Factor Alpha Cytotoxicity. J Virol. 2020; 94(21): e00603-20. https://doi.org/10.1128/jvi.00603-20.
Coope A, Pascoal LB, da Silva FAR, Botezelli JD, Ayrizono MLS, Milanski M, et al. Transcriptional and Molecular Pathways Activated in Mesenteric Adipose Tissue and Intestinal Mucosa of Crohn’s Disease Patients. Int J Inflam. 2017; 2017: 7646859. https://doi.org/10.1155/2017/7646859.
Nakano K, Yamaoka K, Hanami K, Saito K, Sasaguri Y, Yanagihara N, et al. Dopamine induces IL -6-dependent IL -17 production via D1-like receptor on CD4 naive T cells and D1-like receptor antagonist SCH- 23390 inhibits cartilage destruction in a human rheumatoid arthritis/SCID mouse chimera model. J Immunol. 2011; 186(6): 3745-3752. https://doi.org/10.4049/jim-munol.1002475.
García de Tena J, Manzano L, Leal JC, San Antonio E, Sualdea V, Alvarez-Mon M. Distinctive pattern of cytokine production and adhesion molecule expression in peripheral blood memory CD4+ T cells from patients with active Crohn’s disease. J Clin Immunol. 2006; 26(3): 233-242. https://doi.org/10.1007/s10875-006-9016-4.
Jones SC, Evans SW, Lobo AJ, Ceska M, Axon AT, Whicher JT. Serum interleukin-8 in inflammatory bowel disease. J Gastroenterol Hepatol. 1993; 8(6): 508-512. https://doi.org/10.1111/j.1440-1746.1993.tb01643.x.
Freire PP, Cury SS, Lopes LO, Fernandez GJ, Liu J, de Moraes LN, et al. Decreased miR-497-5p Suppresses IL -6 Induced Atrophy in Muscle Cells. Cells. 2021; 10(12):3527. https://doi.org/10.3390/cells10123527.
Brandt M, Grazioso TP, Fawal MA, Tummala KS, Torres-Ruiz R, Rodriguez-Perales S, et al. mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis. Cell Metab. 2018. 27(1): 118-135.e8. https://doi.org/10.1016/j.met.2017.11.006.
Zhang D, Liu J, Lv L, Chen X, Qian Y, Zhao P, et al. Total flavone of Abelmoschus manihot regulates autophagy through the AMPK/mTOR signaling pathway to treat intestinal fibrosis in Crohn’s disease. J Gastroenterol Hepatol. 2024; 39(8): 1586-1596. https://doi.org/10.1111/jgh.16560.
Wang Y, Liu H, Zhang Z, Bian D, Shao K, Wang S, et al. G-MDSC-derived exosomes mediate the differentiation of M-MDSC into M2 macrophages promoting colitis-to-cancer transition. J Immunother Cancer. 2023; 11(6): e006166. https://doi.org/10.1136/jitc-2022-006166.
Gyamfi J, Lee YH, Eom M, Choi J. Inter- leukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal tran- sition in breast cancer cells. Sci Rep. 2018; 8(1): 8859. https://doi.org/10.1038/s41598-018-27184-9.
Akanda MR, Nam HH, Tian W, Islam A, Choo BK, Park BY. Regulation of JAK2/ STAT3 and NF-κB signal transduction pathways; Veronica polita alleviates dextran sulfate sodium-induced murine colitis. Biomed Pharmacother. 2018; 100:296-303. https://doi.org/10.1016/j.bio-pha.2018.01.168.
Kaur S, Bansal Y, Kumar R, Bansal G. A panoramic review of IL -6: Structure, pathophysiological roles and inhibitors. Bioorg Med Chem. 2020; 28(5): 115327. https://doi.org/10.1016/j.bmc.2020.115327.
Lomer MC, Thompson RP, Powell JJ. Fine and ultrafine particles of the diet: influence on the mucosal immune response and association with Crohn’s disease. Proc Nutr Soc. 2002; 61(1): 123-130. https://doi.org/10.1079/pns2001134.
Zhao J, Wang H, Yang H, Zhou Y, Tang L. Autophagy induction by rapamycin ameliorates experimental colitis and improves intestinal epithelial barrier function in IL -10 knockout mice. Int Immunopharmacol. 2020; 81: 105977. https://doi.org/10.1016/j.intimp.2019.105977.
Long SH, He Y, Chen MH, Cao K, Chen YJ, Chen BL, et al. Activation of PI3K/ Akt/mTOR signaling pathway triggered by PTEN downregulation in the pathogenesis of Crohn’s disease. J Dig Dis. 2013; 14(12): 662-669. https://doi.org/10.1111/1751-2980.12095.
Li L, Wan G, Han B, Zhang Z. Echinacoside alleviated LPS-induced cell apoptosis and inflammation in rat intestine epithelial cells by inhibiting the mTOR/STAT3 pathway. Biomed Pharmacother. 2018; 104: 622-628. https://doi.org/10.1016/j.biopha.2018.05.072.
Li F, Yin YK, Zhang JT, Gong HP, Hao XD. Role of circular RNAs in retinoblastoma. Funct Integr Genomics. 2022; 23(1): 13. https://doi.org/10.1007/s10142-022-00942-9.
Li L, Zhang Q and Lian K. Circular RNA circ_0000284 plays an oncogenic role in the progression of non-small cell lung cancer through the miR-377-3p-mediated PD-L1 promotion. Cancer Cell Int. 2020; 20: 247. https://doi.org/10.1186/s12935-020-01310-y.
Zhang M, Han Y, Zhai Y, Ma X, An X, Zhang S, et al. Integrative analysis of circRNAs, miRNAs, and mRNAs profiles to reveal ceRNAs networks in chicken intra-muscular and abdominal adipogenesis. BMC Genomics. 2020; 21(1): 594. https://doi.org/10.1186/s12864-020-07000-3.
Pan H, Li T, Jiang Y, Pan C, Ding Y, Huang Z, et al. Overexpression of Circular RNA ciRS-7 Abrogates the Tumor Suppressive Effect of miR-7 on Gastric Cancer via PTEN/PI3K/AKT Signaling Pathway. J Cell Biochem. 2018; 119(1): 440-446. https://doi.org/10.1002/jcb.26201.
Zhang Y, Li C, Liu X, Wang Y, Zhao R, Yang Y, et al. circHIPK3 promotes oxaliplatin-resistance in colorectal cancer through autophagy by sponging miR-637. EBio- Medicine. 2019; 48: 277-288. https://doi.org/10.1016/j.ebiom.2019.09.051.
Ye Y, Zhang L, Hu T, Yin J, Xu L, Pang Z, et al. CircRNA_103765 acts as a proinflammatory factor via sponging miR-30 family in Crohn’s disease. Sci Rep. 2021; 11(1): 565. https://doi.org/10.1038/s41598-020-80663-w.
Wu F, Guo NJ, Tian H, Marohn M, Gearhart S, Bayless TM, et al. Peripheral blood microRNAs distinguish active ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis. 2011; 17(1): 241-250. https://doi.org/10.1002/ibd.21450.
Syed NH, Mussa A, Elmi AH, Jamal Al-Khreisat M, Ahmad Mohd Zain MR, Nurul AA. Role of MicroRNAs in Inflammatory Joint Diseases: A Review. Immunol Invest. 2024; 53(2): 185-209. https://doi.org/10.1080/08820139.2023.2293095.
Ke J, Chen M, Ma S, Zhang L, Zhang L. Circular R-NA VMA21 ameliorates lung injury in septic rat via targeting microRNA-497-5p/CD2-associated protein axis. Bioengineered. 2022; 13(3): 5453-5466. https://doi.org/10.1080/21655979.2022.2031406.
Lou W, Yan J, Wang W. Downregulation of miR-497-5p Improves Sepsis-Induced Acute Lung Injury by Targeting IL2RB. Biomed Res Int. 2021; 2021: 6624702. https://doi.org/10.1155/2021/6624702.
Zhang M, Yang D, Yu H, Li Q. MicroR-NA-497 inhibits inflammation in DSS- induced IBD model mice and lipopoly- saccharide-induced RAW264.7 cells via Wnt/β-catenin pathway. Int Immunopharmacol. 2021; 101(Pt B): 108318. https://doi.org/10.1016/j.intimp.2021.108318.
Ma YS, Cao YF, Liu JB, Li W, Deng J, Yang XL, et al. The power and the promise of circRNAs for cancer precision medicine with functional diagnostics and prognostic prediction. Carcinogenesis. 2021; 42(11):1305-1313. https://doi.org/10.1093/carcin/bgab071.
Yin J, Hu T, Xu L, Li P, Li M, Ye Y, et al. Circular RNA expression profile in peripheral blood mononuclear cells from Crohn disease patients. Medicine (Baltimore). 2019; 98(26): e16072. https://doi.org/10.1097/md.0000000000016072.
Lu JW, Rouzigu A, Teng LH, Liu WL. The Construction and Comprehensive Analysis of Inflammation-Related ceRNA Networks and Tissue-Infiltrating Immune Cells in Ulcerative Progression. Biomed Res Int. 2021; 2021: 6633442. https://doi.org/10.1155/2021/6633442.
Qiao YQ, Cai CW, Shen J, Zheng Q, Ran ZH. Circular RNA expression alterations in colon tissues of Crohn’s disease patients. Mol Med Rep. 2019; 19(5): 4500-4506. https://doi.org/10.3892/mmr.2019.10070.
Zhu Y, Mahon BD, Froicu M, Cantorna MT. Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Eur J Immunol. 2005; 35(1): 217-224. https://doi.org/10.1002/eji.200425491.
Sun L, Rollins D, Qi Y, Fredericks J, Mansell TJ, Jergens A, et al. TNFα regulates intestinal organoids from mice with both defined and conventional microbiota. Int J Biol Macromol. 2020; 164: 548-556. https://doi.org/10.1016/j.ijbiomac.2020.07.176.
Kaminsky LW, Al-Sadi R, Ma TY. IL -1β and the Intestinal Epithelial Tight Junction Barrier. Front Immunol. 2021; 12:767456. https://doi.org/10.3389/fimmu.2021.767456.
Van Winkle JA, Constant DA, Li L, Nice TJ. Selective Interferon Responses of Intestinal Epithelial Cells Minimize Tumor Necrosis Factor Alpha Cytotoxicity. J Virol. 2020; 94(21): e00603-20. https://doi.org/10.1128/jvi.00603-20.
Coope A, Pascoal LB, da Silva FAR, Botezelli JD, Ayrizono MLS, Milanski M, et al. Transcriptional and Molecular Pathways Activated in Mesenteric Adipose Tissue and Intestinal Mucosa of Crohn’s Disease Patients. Int J Inflam. 2017; 2017: 7646859. https://doi.org/10.1155/2017/7646859.
Nakano K, Yamaoka K, Hanami K, Saito K, Sasaguri Y, Yanagihara N, et al. Dopamine induces IL -6-dependent IL -17 production via D1-like receptor on CD4 naive T cells and D1-like receptor antagonist SCH- 23390 inhibits cartilage destruction in a human rheumatoid arthritis/SCID mouse chimera model. J Immunol. 2011; 186(6): 3745-3752. https://doi.org/10.4049/jim-munol.1002475.
García de Tena J, Manzano L, Leal JC, San Antonio E, Sualdea V, Alvarez-Mon M. Distinctive pattern of cytokine production and adhesion molecule expression in peripheral blood memory CD4+ T cells from patients with active Crohn’s disease. J Clin Immunol. 2006; 26(3): 233-242. https://doi.org/10.1007/s10875-006-9016-4.
Jones SC, Evans SW, Lobo AJ, Ceska M, Axon AT, Whicher JT. Serum interleukin-8 in inflammatory bowel disease. J Gastroenterol Hepatol. 1993; 8(6): 508-512. https://doi.org/10.1111/j.1440-1746.1993.tb01643.x.
Freire PP, Cury SS, Lopes LO, Fernandez GJ, Liu J, de Moraes LN, et al. Decreased miR-497-5p Suppresses IL -6 Induced Atrophy in Muscle Cells. Cells. 2021; 10(12):3527. https://doi.org/10.3390/cells10123527.
Brandt M, Grazioso TP, Fawal MA, Tummala KS, Torres-Ruiz R, Rodriguez-Perales S, et al. mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis. Cell Metab. 2018. 27(1): 118-135.e8. https://doi.org/10.1016/j.met.2017.11.006.
Zhang D, Liu J, Lv L, Chen X, Qian Y, Zhao P, et al. Total flavone of Abelmoschus manihot regulates autophagy through the AMPK/mTOR signaling pathway to treat intestinal fibrosis in Crohn’s disease. J Gastroenterol Hepatol. 2024; 39(8): 1586-1596. https://doi.org/10.1111/jgh.16560.
Wang Y, Liu H, Zhang Z, Bian D, Shao K, Wang S, et al. G-MDSC-derived exosomes mediate the differentiation of M-MDSC into M2 macrophages promoting colitis-to-cancer transition. J Immunother Cancer. 2023; 11(6): e006166. https://doi.org/10.1136/jitc-2022-006166.
Gyamfi J, Lee YH, Eom M, Choi J. Inter- leukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal tran- sition in breast cancer cells. Sci Rep. 2018; 8(1): 8859. https://doi.org/10.1038/s41598-018-27184-9.
Akanda MR, Nam HH, Tian W, Islam A, Choo BK, Park BY. Regulation of JAK2/ STAT3 and NF-κB signal transduction pathways; Veronica polita alleviates dextran sulfate sodium-induced murine colitis. Biomed Pharmacother. 2018; 100:296-303. https://doi.org/10.1016/j.bio-pha.2018.01.168.
Kaur S, Bansal Y, Kumar R, Bansal G. A panoramic review of IL -6: Structure, pathophysiological roles and inhibitors. Bioorg Med Chem. 2020; 28(5): 115327. https://doi.org/10.1016/j.bmc.2020.115327.
Publicado
2025-12-08
Cómo citar
Yin, X., Huang, G., Zheng, C., Zhou, Y., & Chen, R. (2025). CircRNA_104293 targets miR-497-5p to inhibit the mTOR/STAT3 pathway and mitigate inflammation in Crohn’s disease.: CircRNA_104293 actúa sobre el miR-497-5p para inhibir la vía mTOR/STAT3 y mitigar la inflamación en la enfermedad de Crohn. Investigación Clínica, 66(4), 365-377. https://doi.org/10.54817/IC.v66n4a02
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