Role of long non‑coding RNA MALAT1 in chronic obstructive pulmonary disease

Hu,Tian‑Jun; Huang,Hong‑Bo; Shen,Hai‑Bo; Chen,Wei; Yang,Zhen‑Hua

doi:10.3892/etm.2020.8996

Role of long non‑coding RNA MALAT1 in chronic obstructive pulmonary disease

Authors:
- Tian‑Jun Hu
- Hong‑Bo Huang
- Hai‑Bo Shen
- Wei Chen
- Zhen‑Hua Yang
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Affiliations: Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315012, P.R. China, Zhongyuan Union Clinical Laboratory Co. Ltd., Tianjin 300384, P.R. China
Published online on: July 13, 2020 https://doi.org/10.3892/etm.2020.8996
Pages: 2691-2697
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Chronic obstructive pulmonary disease (COPD) is a pathological inflammatory condition of the lungs that is associated with high rates of mortality. Although long non‑coding RNAs (lncRNAs) serve a role in lung diseases, their functions in COPD pathogenesis are relatively unknown. The present study aimed to assess the role of differentially expressed lncRNAs in COPD. Expression profile analysis of six lncRNAs in age‑matched COPD and non‑COPD tissues were conducted. Among the six tested lncRNAs, metastasis‑associated in lung adenocarcinoma transcript 1 (MALAT1) was the most consistently overexpressed in COPD lung tissue specimens. To model COPD in vitro, human lung fibroblasts were treated with transforming growth factor‑β (TGF‑β) and MALAT1 was knocked down by small interfering RNA. This promoted cell viability and concurrently inhibited the expression of mesenchymal proteins, fibronectin and α‑smooth muscle actin. In COPD, cell senescence is linked to the activation of mammalian target of rapamycin complex 1 (mTORC1). Upon gene silencing of MALAT1 in non‑TGF‑β‑treated cells, cells demonstrated constitutive activation of mTORC1, which was assessed by the protein expression levels of mTORC1 substrate S6 kinase (S6K1). By contrast, upon MALAT1 silencing in the TGF‑β‑treated cells, mTORC1 activation was not suppressed, despite the mesenchymal cell markers protein expression levels being downregulated. Thus, lncRNA MALAT1 may represent a potent biomarker in COPD patients and may act as a target for both diagnostic and therapeutic purposes.

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1	Demedts IK, Demoor T, Bracke KR, Joos GF and Brusselle GG: Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res. 7(53)2006.PubMed/NCBI View Article : Google Scholar
2	Demedts IK, Brusselle GG, Bracke KR, Vermaelen KY and Pauwels RA: Matrix metalloproteinases in asthma and COPD. Curr Opin Pharmacol. 5:257–263. 2005.PubMed/NCBI View Article : Google Scholar
3	Barnes PJ, Shapiro SD and Pauwels RA: Chronic obstructive pulmonary disease: Molecular and cellularmechanisms. Eur Respir J. 22:672–688. 2003.PubMed/NCBI View Article : Google Scholar
4	Pauwels RA, Buist AS, Calverley PM, Jenkins CR and Hurd SS: GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO global initiative for chronic obstructive lung disease (GOLD) workshop summary. Am J Respir Crit Care Med. 163:1256–1276. 2001.PubMed/NCBI View Article : Google Scholar
5	Pauwels RA and Rabe KF: Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet. 364:613–620. 2004.PubMed/NCBI View Article : Google Scholar
6	Lahzami S and Aubert JD: Lung transplantation for COPD-evidence-based. Swiss Med Wkly. 139:4–8. 2009.PubMed/NCBI
7	Chilosi M, Poletti V and Rossi A: The pathogenesis of COPD and IPF: Distinct horns of the same devil? Respir Res. 13(3)2012.PubMed/NCBI View Article : Google Scholar
8	Houssaini A, Breau M, Kebe K, Abid S, Marcos E, Lipskaia L, Rideau D, Parpaleix A, Huang J, Amsellem V, et al: mTOR pathway activation drives lung cell senescence and emphysema. JCI Insight. 3(pii: 93203)2018.PubMed/NCBI View Article : Google Scholar
9	Malone CD and Hannon GJ: Small RNAs as guardians of the genome. Cell. 136:656–668. 2009.PubMed/NCBI View Article : Google Scholar
10	Moazed D: Small RNAs in transcriptional gene silencing and genome defence. Nature. 457:413–420. 2009.PubMed/NCBI View Article : Google Scholar
11	Brosnan CA and Voinnet O: The long and the short of noncoding RNAs. Curr Opin Cell Biol. 21:416–425. 2009.PubMed/NCBI View Article : Google Scholar
12	Mattick JS: Non-coding RNAs: The architects of eukaryotic complexity. EMBO Rep. 2:986–991. 2001.PubMed/NCBI View Article : Google Scholar
13	Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E and Chang HY: Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 129:1311–1323. 2007.PubMed/NCBI View Article : Google Scholar
14	Kim A, Zhao H, Ifrim I and Dean A: Beta-globin intergenic transcription and histone acetylation dependent on an enhancer. Mol Cell Biol. 27:2980–2986. 2007.PubMed/NCBI View Article : Google Scholar
15	Managadze D, Rogozin IB, Chernikova D, Shabalina SA and Koonin EV: Negative correlation between expression level and evolutionary rate of long intergenic noncoding RNAs. Genome Biol Evol. 3:1390–1404. 2011.PubMed/NCBI View Article : Google Scholar
16	Krangel MS: T cell development: Better living through chromatin. Nat Immunol. 8:687–694. 2007.PubMed/NCBI View Article : Google Scholar
17	Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L, Livezey JR, Connell T, Sesterhenn IA, Yoshino K, et al: PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci USA. 97:12216–12221. 2000.PubMed/NCBI View Article : Google Scholar
18	Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, Debruyne FM, Ru N and Isaacs WB: DD3: A new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 59:5975–5979. 1999.PubMed/NCBI
19	Petrovics G, Zhang W, Makarem M, Street JP, Connelly R, Sun L, Sesterhenn IA, Srikantan V, Moul JW and Srivastava S: Elevated expression of PCGEM1, a prostate-specific gene with cell growth-promoting function, is associated with high-risk prostate cancer patients. Oncogene. 23:605–611. 2004.PubMed/NCBI View Article : Google Scholar
20	Iacoangeli A, Lin Y, Morley EJ, Muslimov IA, Bianchi R, Reilly J, Weedon J, Diallo R, Böcker W and Tiedge H: BC200 RNA in invasive and preinvasive breast cancer. Carcinogenesis. 25:2125–2133. 2004.PubMed/NCBI View Article : Google Scholar
21	Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, et al: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 464:1071–1076. 2010.PubMed/NCBI View Article : Google Scholar
22	Taft RJ, Pang KC, Mercer TR, Dinger M and Mattick JS: Non-coding RNAs: Regulators of disease. J Pathol. 220:126–139. 2010.PubMed/NCBI View Article : Google Scholar
23	Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S, et al: Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell. 152:570–583. 2013.PubMed/NCBI View Article : Google Scholar
24	Gutschner T, Hämmerle M, Eissmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Gross M, et al: The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 73:1180–1189. 2013.PubMed/NCBI View Article : Google Scholar
25	Johnson R: Long non-coding RNAs in Huntington's disease neurodegeneration. Neurobiol Dis. 46:245–254. 2012.PubMed/NCBI View Article : Google Scholar
26	Congrains A, Kamide K, Oguro R, Yasuda O, Miyata K, Yamamoto E, Kawai T, Kusunoki H, Yamamoto H, Takeya Y, et al: Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. Atherosclerosis. 220:449–455. 2012.PubMed/NCBI View Article : Google Scholar
27	Tang W, Shen Z, Guo J and Sun S: Screening of long non-coding RNA and TUG1 inhibits proliferation with TGF-β induction in patients with COPD. Int J Chron Obstruct Pulmon Dis. 11:2951–2964. 2016.PubMed/NCBI View Article : Google Scholar
28	Li JY, Chen XX, Lu XH, Zhang CB, Shi QP and Feng L: Elevated RBP4 plasma levels were associated with diabetic retinopathy in type 2 diabetes. Biosci Rep. 38(pii: BSR20181100)2018.PubMed/NCBI View Article : Google Scholar
29	Li S, Mei Z, Hu HB and Zhang X: The lncRNA MALAT1 contributes to non-small cell lung cancer development via modulating miR-124/STAT3 axis. J Cell Physiol. 233:6679–6688. 2018.PubMed/NCBI View Article : Google Scholar
30	Sun C, Li S, Zhang F, Xi Y, Wang L, Bi Y and Li D: Long non-coding RNA NEAT1 promotes non-small cell lung cancer progression through regulation of miR-377-3p-E2F3 pathway. Oncotarget. 7:51784–51814. 2016.PubMed/NCBI View Article : Google Scholar
31	Nie W, Ge HJ, Yang XQ, Sun X, Huang H, Tao X, Chen WS and Li B: LncRNA-UCA1 exerts oncogenic functions in non-small cell lung cancer by targeting miR-193a-3p. Cancer Lett. 371:99–106. 2016.PubMed/NCBI View Article : Google Scholar
32	Loewen G, Jayawickramarajah J, Zhuo Y and Shan B: Functions of lncRNA HOTAIR in lung cancer. J Hematol Oncol. 7(90)2014.PubMed/NCBI View Article : Google Scholar
33	Yu G, Liu J, Xu K and Dong J: Uncoupling protein 2 mediates resistance to gemcitabine-induced apoptosis in hepatocellular carcinoma cell lines. Biosci Rep. 35(pii: e00231)2015.PubMed/NCBI View Article : Google Scholar
34	Xia S, Ji R and Zhan W: Long noncoding RNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) inhibits proliferation and invasion of glioma cells by suppressing the Wnt/β-catenin signaling pathway. BMC Neurol. 17(30)2017.PubMed/NCBI View Article : Google Scholar
35	Zhong Y, Chen Z, Guo S, Liao X, Xie H, Zheng Y, Cai B, Huang P, Liu Y, Zhou Q, et al: TUG1, SPRY4-IT1, and HULC as valuable prognostic biomarkers of survival in cancer: A PRISMA-compliant meta-analysis. Medicine (Baltimore). 96(e8583)2017.PubMed/NCBI View Article : Google Scholar
36	Perez DS, Hoage TR, Pritchett JR, Ducharme-Smith AL, Halling ML, Ganapathiraju SC, Streng PS and Smith DI: Long, abundantly expressed non-coding transcripts are altered in cancer. Hum Mol Genet. 17:642–655. 2008.PubMed/NCBI View Article : Google Scholar
37	Guttman M, Donaghey J, Carey BW, Garber M, Grenier JK, Munson G, Young G, Lucas AB, Ach R, Bruhn L, et al: lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature. 477:295–300. 2011.PubMed/NCBI View Article : Google Scholar
38	Ponting CP, Oliver PL and Reik W: Evolution and functions of long noncoding RNAs. Cell. 136:629–641. 2009.PubMed/NCBI View Article : Google Scholar
39	Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, Daughters RS, Chen G, Weatherspoon MR, Clark HB, Ebner TJ, et al: Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat Genet. 38:758–769. 2006.PubMed/NCBI View Article : Google Scholar
40	Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit Care Med 152: S77-S121, 1995.
41	Buist AS: Guidelines for the management of chronic obstructive pulmonary disease. Respir Med. 96 (Suppl C):S11–S16. 2002.PubMed/NCBI View Article : Google Scholar
42	Jones PW, Quirk FH, Baveystock CM and Littlejohns P: A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis. 145:1321–1327. 1992.PubMed/NCBI View Article : Google Scholar
43	Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ and Wedzicha JA: Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 157:1418–1422. 1998.PubMed/NCBI View Article : Google Scholar
44	De Smet EG, Mestdagh P, Vandesompele J, Brusselle GG and Bracke KR: Non-coding RNAs in the pathogenesis of COPD. Thorax. 70:782–791. 2015.PubMed/NCBI View Article : Google Scholar
45	Cao G, Zhang J, Wang M, Song X, Liu W, Mao C and Lv C: Differential expression of long non-coding RNAs in bleomycin-induced lung fibrosis. Int J Mol Med. 32:355–364. 2013.PubMed/NCBI View Article : Google Scholar
46	McKiernan PJ, Molloy K, Cryan SA, McElvaney NG and Greene CM: Long noncoding RNA are aberrantly expressed in vivo in the cystic fibrosis bronchial epithelium. Int J Biochem Cell Biol. 52:184–191. 2014.PubMed/NCBI View Article : Google Scholar
47	Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E, et al: MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 22:8031–8041. 2003.PubMed/NCBI View Article : Google Scholar
48	Bi H, Zhou J, Wu D, Gao W, Li L, Yu L, Liu F, Huang M, Adcock IM, Barnes PJ and Yao X: Microarray analysis of long non-coding RNAs in COPD lung tissue. Inflamm Res. 64:119–126. 2015.PubMed/NCBI View Article : Google Scholar
49	Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW and Tracey KJ: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 405:458–462. 2000.PubMed/NCBI View Article : Google Scholar
50	Qi JD, Chu YF, Zhang GY, Li HJ, Yang DD and Wang Q: Down-regulated LncR-MALAT1 suppressed cell proliferation and migration by inactivating autophagy in bladder cancer. RSC Adv. 8:31019–31027. 2018.