MicroRNA‑138‑5p regulates the development of spinal cord injury by targeting SIRT1

Chen,Jinchuan; Qin,Rujie

doi:10.3892/mmr.2020.11071

MicroRNA‑138‑5p regulates the development of spinal cord injury by targeting SIRT1

Authors:
- Jinchuan Chen
- Rujie Qin
View Affiliations

Affiliations: Department of Spine Surgery, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222000, P.R. China
Published online on: April 16, 2020 https://doi.org/10.3892/mmr.2020.11071
Pages: 328-336
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

MicroRNAs (miRs) play an important role in the development and progression of spinal cord injury (SCI). The role of miR‑138‑5p in SCI was investigated in the present study. The anti‑inflammatory effects of miR‑138‑5p and underlying mechanisms were investigated in an SCI rat model and in vitro model. Reverse transcription‑quantitative PCR (RT‑qPCR) was used to examine the expression of miR‑138‑5p in the SCI in vivo and in vitro models, as well as patients with SCI; it was found that miR‑138‑5p was significantly upregulated in SCI. Bioinformatics and dual‑luciferase reporter assays were performed to predict and confirm the binding sites between miR‑138‑5p and the 3'untranslated region of sirtuin 1 (SIRT1). Then, the expression of SIRT1 was detected via RT‑qPCR and western blotting, indicating downregulation of SIRT1 in SCI. PC12 cells were transfected with miR‑138‑5p inhibitor, inhibitor control or miR‑138‑5p inhibitor + SIRT1 small interfering RNA for 48 h, and then subjected to lipopolysaccharide (100 ng/ml) treatment for 4 h. Then, MTT assay, flow cytometry and ELISA experiments were performed to analyze cell viability, apoptosis, and the levels of tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6. Findings suggested that downregulation of miR‑138‑5p increased PC12 cell viability, inhibited cell apoptosis and attenuated proinflammatory responses, which may result in amelioration of SCI. However, all these effects were reversed by SIRT1 knockdown. Finally, it was observed that miR‑138‑5p altered the related protein expression of the PTEN/AKT pathway. These results indicated that miR‑138‑5p could regulate inflammatory responses and cell apoptosis in SCI models by modulating the PTEN/AKT signaling pathway via SIRT1, thus playing an important role in the development of SCI. Collectively, the present study demonstrated that miR‑138‑5p may be a novel therapeutic target for the treatment of SCI.

View Figures

View References

1	Silva NA, Sousa N, Reis RL and Salgado AJ: From basics to clinical: A comprehensive review on spinal cord injury. Prog Neurobiol. 114:25–57. 2014. View Article : Google Scholar : PubMed/NCBI
2	Brommer B, Engel O, Kopp MA, Watzlawick R, Müller S, Prüss H, Chen Y, DeVivo MJ, Finkenstaedt FW, Dirnagl U, et al: Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. Brain. 139:692–707. 2016. View Article : Google Scholar : PubMed/NCBI
3	Siddall PJ, McIndoe L, Austin P and Wrigley PJ: The impact of pain on spiritual well-being in people with a spinal cord injury. Spinal Cord. 55:105–111. 2017. View Article : Google Scholar : PubMed/NCBI
4	Ahmed MM, King KC, Pearce SM, Ramsey MA, Miranpuri GS and Resnick DK: Novel targets for spinal cord injury related neuropathic pain. Ann Neurosci. 18:162–167. 2011. View Article : Google Scholar : PubMed/NCBI
5	Hooshmand MJ, Galvan MD, Partida E and Anderson AJ: Characterization of recovery, repair, and inflammatory processes following contusion spinal cord injury in old female rats: Is age a limitation? Immun Ageing. 11:152014. View Article : Google Scholar : PubMed/NCBI
6	Garshick E, Stolzmann KL, Gagnon DR, Morse LR and Brown R: Systemic inflammation and reduced pulmonary function in chronic spinal cord injury. PM R. 3:433–439. 2011. View Article : Google Scholar : PubMed/NCBI
7	Gris D, Hamilton EF and Weaver LC: The systemic inflammatory response after spinal cord injury damages lungs and kidneys. Exp Neurol. 211:259–270. 2008. View Article : Google Scholar : PubMed/NCBI
8	Pillai RS: MicroRNA function: Multiple mechanisms for a tiny RNA? RNA. 11:1753–1761. 2005. View Article : Google Scholar : PubMed/NCBI
9	Hammond SM: An overview of microRNAs. Adv Drug Deliv Rev. 87:3–14. 2015. View Article : Google Scholar : PubMed/NCBI
10	Shukla GC, Singh J and Barik S: MicroRNAs: Processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol. 3:83–92. 2011.PubMed/NCBI
11	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
12	Feng W and Feng Y: MicroRNAs in neural cell development and brain diseases. Sci China Life Sci. 54:1103–1112. 2011. View Article : Google Scholar : PubMed/NCBI
13	Bian S and Sun T: Functions of noncoding RNAs in neural development and neurological diseases. Mol Neurobiol. 44:359–373. 2011. View Article : Google Scholar : PubMed/NCBI
14	Papagiannakopoulos T and Kosik KS: MicroRNAs: Regulators of oncogenesis and stemness. BMC Med. 6:152008. View Article : Google Scholar : PubMed/NCBI
15	Blandino G, Fazi F, Donzelli S, Kedmi M, Sas-Chen A, Muti P, Strano S and Yarden Y: Tumor suppressor microRNAs: A novel non-coding alliance against cancer. FEBS Lett. 588:2639–2652. 2014. View Article : Google Scholar : PubMed/NCBI
16	Palanichamy JK and Rao DS: miRNA dysregulation in cancer: Towards a mechanistic understanding. Front Genet. 5:542014. View Article : Google Scholar : PubMed/NCBI
17	Wang Y, Kim S and Kim IM: Regulation of metastasis by microRNAs in ovarian cancer. Front Oncol. 4:1432014. View Article : Google Scholar : PubMed/NCBI
18	Othman N and Nagoor NH: The role of microRNAs in the regulation of apoptosis in lung cancer and its application in cancer treatment. Biomed Res Int. 2014:3180302014. View Article : Google Scholar : PubMed/NCBI
19	Han C, Yu Z, Duan Z and Kan Q: Role of microRNA-1 in human cancer and its therapeutic potentials. Biomed Res Int. 2014:4283712014. View Article : Google Scholar : PubMed/NCBI
20	Liu NK, Wang XF, Lu QB and Xu XM: Altered microRNA expression following traumatic spinal cord injury. Exp Neurol. 219:424–429. 2009. View Article : Google Scholar : PubMed/NCBI
21	Roberto GM, Lira RC, Delsin LE, Vieira GM, Silva MO, Hakime RG, Yamashita ME, Engel EE, Scrideli CA, Tone LG and Brassesco MS: microRNA-138-5p as a worse prognosis biomarker in pediatric, adolescent, and young adult osteosarcoma. Pathol Oncol Res. Mar 12–2019.doi: 10.1007/s12253-019-00633-0. [Epub ahead of print].
22	He Z, Ruan X, Liu X, Zheng J, Liu Y, Liu L, Ma J, Shao L, Wang D, Shen S, et al: FUS/circ_002136/miR-138-5p/SOX13 feedback loop regulates angiogenesis in Glioma. J Exp Clin Cancer Res. 38:652019. View Article : Google Scholar : PubMed/NCBI
23	Zhu D, Gu L, Li Z, Jin W, Lu Q and Ren T: MiR-138-5p suppresses lung adenocarcinoma cell epithelial-mesenchymal transition, proliferation and metastasis by targeting ZEB2. Pathol Res Pract. 215:861–872. 2019. View Article : Google Scholar : PubMed/NCBI
24	Ma J, Zhang Y, Ji H, Chen L, Chen T, Guo C, Zhang S, Jia J and Niu P: Overexpression of miR-138-5p suppresses MnCl2 -induced autophagy by targeting SIRT1 in SH-SY5Y cells. Environ Toxicol. 34:539–547. 2019. View Article : Google Scholar : PubMed/NCBI
25	Nogueiras R, Habegger KM, Chaudhary N, Finan B, Banks AS, Dietrich MO, Horvath TL, Sinclair DA, Pfluger PT and Tschöp MH: Sirtuin 1 and sirtuin 3: Physiological modulators of metabolism. Physiol Rev. 92:1479–1514. 2012. View Article : Google Scholar : PubMed/NCBI
26	da Cunha MSB and Arruda SF: Tucum-do-Cerrado (Bactris setosa Mart.) may promote anti-aging effect by upregulating SIRT1-Nrf2 pathway and attenuating oxidative stress and inflammation. Nutrients. 9:E12432017. View Article : Google Scholar : PubMed/NCBI
27	Rada P, Pardo V, Mobasher MA, García-Martínez I, Ruiz L, González-Rodríguez Á, Sanchez-Ramos C, Muntané J, Alemany S, James LP, et al: SIRT1 controls acetaminophen hepatotoxicity by modulating inflammation and oxidative stress. Antioxid Redox Signal. 28:1187–1208. 2018. View Article : Google Scholar : PubMed/NCBI
28	Chan SH, Hung CH, Shih JY, Chu PM, Cheng YH, Lin HC and Tsai KL: SIRT1 inhibition causes oxidative stress and inflammation in patients with coronary artery disease. Redox Biol. 13:301–309. 2017. View Article : Google Scholar : PubMed/NCBI
29	Cheng YY, Kao CL, Ma HI, Hung CH, Wang CT, Liu DH, Chen PY and Tsai KL: SIRT1-related inhibition of pro-inflammatory responses and oxidative stress are involved in the mechanism of nonspecific low back pain relief after exercise through modulation of Toll-like receptor 4. J Biochem. 158:299–308. 2015. View Article : Google Scholar : PubMed/NCBI
30	Roberts TT, Leonard GR and Cepela DJ: Classifications in brief: American spinal injury association (ASIA) impairment scale. Clin Orthop Relat Res. 475:1499–1504. 2017. View Article : Google Scholar : PubMed/NCBI
31	Bayne K: Revised guide for the care and use of laboratory animals available. American Physiological Society. Physiologist. 39:199208–199211. 1996.
32	Xin DQ, Hu ZM, Huo HJ, Yang XJ, Han D, Xing WH, Zhao Y and Qiu QH: Schisandrin B attenuates the inflammatory response, oxidative stress and apoptosis induced by traumatic spinal cord injury via inhibition of p53 signaling in adult rats. Mol Med Rep. 16:533–538. 2017. View Article : Google Scholar : PubMed/NCBI
33	Tan Y, Yu L, Zhang C, Chen K, Lu J and Tan L: miRNA-146a attenuates inflammation in an in vitro spinal cord injury model via inhibition of TLR4 signaling. Exp Ther Med. 16:3703–3709. 2018.PubMed/NCBI
34	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
35	Wang C, Pan Y, Cheng B, Chen J and Bai B: Identification of conserved and novel microRNAs in cerebral ischemia-reperfusion injury of rat using deep sequencing. J Mol Neurosci. 54:671–683. 2014. View Article : Google Scholar : PubMed/NCBI
36	Wan G, An Y, Tao J, Wang Y, Zhou Q, Yang R and Liang Q: MicroRNA-129-5p alleviates spinal cord injury in mice via suppressing the apoptosis and inflammatory response through HMGB1/TLR4/NF-κB pathway. Biosci Rep. 40:BSR201933152020. View Article : Google Scholar : PubMed/NCBI
37	Sun F, Li SG, Zhang HW, Hua FW, Sun GZ and Huang Z: MiRNA-411 attenuates inflammatory damage and apoptosis following spinal cord injury. Eur Rev Med Pharmacol Sci. 24:491–498. 2020.PubMed/NCBI
38	Weishaupt N, Silasi G, Colbourne F and Fouad K: Secondary damage in the spinal cord after motor cortex injury in rats. J Neurotrauma. 27:1387–1397. 2010. View Article : Google Scholar : PubMed/NCBI
39	Wang B, Wang D, Yan T and Yuan H: MiR-138-5p promotes TNF-α-induced apoptosis in human intervertebral disc degeneration by targeting SIRT1 through PTEN/PI3K/Akt signaling. Exp Cell Res. 345:199–205. 2016. View Article : Google Scholar : PubMed/NCBI
40	Tian S, Guo X, Yu C, Sun C and Jiang J: miR-138-5p suppresses autophagy in pancreatic cancer by targeting SIRT1. Oncotarget. 8:11071–11082. 2017. View Article : Google Scholar : PubMed/NCBI
41	Bank M, Stein A, Sison C, Glazer A, Jassal N, McCarthy D, Shatzer M, Hahn B, Chugh R, Davies P and Bloom O: Elevated circulating levels of the pro-inflammatory cytokine macrophage migration inhibitory factor in individuals with acute spinal cord injury. Arch Phys Med Rehabil. 96:633–644. 2015. View Article : Google Scholar : PubMed/NCBI