MiR-509-3-5p-NONHSAT112228.2 Axis Regulates p21 and Suppresses Proliferation and Migration of Lung Cancer Cells

Author(s): Jing-Jing Liang, Jun-Yi Wang, Tong-Jia Zhang, Guo-Shun An, Ju-Hua Ni, Shu-Yan Li*, Hong-Ti Jia

Journal Name: Current Topics in Medicinal Chemistry

Volume 20 , Issue 10 , 2020

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Abstract:

Background: Although the involvement of individual microRNA and lncRNA in the regulation of p21 expression has largely been evidenced, less is known about the roles of functional interactions between miRNAs and lncRNAs in p21 expression. Our previous work demonstrated that miR-509- 3-5p could block cancer cell growth.

Methods: To gain an insight into the role of miR-509-3-5p in the regulation of p21 expression, we performed in silico prediction and showed that miR-509-3-5p might target the NONHSAT112228.2, a sense-overlapping lncRNA transcribed by a non-code gene overlapping with p21 gene. Mutation and luciferase report analysis suggested that miR-509-3-5p could target NONHSAT112228.2, thereby blocking its expression. Consistently, NONHSAT112228.2 expression was inversely correlated with both miR-509-3-5p and p21 expression in cancer cells. Ectopic expression of miR-509-3-5p and knockdown of NONHSAT112228.2 both promoted proliferation and migration of cancer cells.

Results: Interestingly, high-expression of NONHSAT112228.2 accompanied by low-expression of p21 was observed in lung cancer tissues and associated with lower overall survival.

Conclusion: Taken together, our study found a new regulatory pathway of p21, in which MiR-509-3-5p functionally interacts with NONHSAT112228.2 to release p21 expression. MiR-509-3-5p— NONHSAT112228.2 regulatory axis can inhibit the proliferation and migration of lung cancer cells.

Keywords: MiR-509-3-5p, NONHSAT112228.2, p21, Gene regulation, Non-small cell lung cancer, MicroRNAs.

[1]
Liz, J.; Esteller, M. lncRNAs and microRNAs with a role in cancer development. Biochim. Biophys. Acta, 2016, 1859(1), 169-176.
[http://dx.doi.org/10.1016/j.bbagrm.2015.06.015] [PMID: 26149773]
[2]
Bhan, A.; Mandal, S.S. Long noncoding RNAs: emerging stars in gene regulation, epigenetics and human disease. ChemMedChem, 2014, 9(9), 1932-1956.
[http://dx.doi.org/10.1002/cmdc.201300534] [PMID: 24677606]
[3]
Schmitz, S.U.; Grote, P.; Herrmann, B.G. Mechanisms of long noncoding RNA function in development and disease. Cell. Mol. Life Sci., 2016, 73(13), 2491-2509.
[http://dx.doi.org/10.1007/s00018-016-2174-5] [PMID: 27007508]
[4]
Joshi, P.; Middleton, J.; Jeon, Y.J.; Garofalo, M. MicroRNAs in lung cancer. World J. Methodol., 2014, 4(2), 59-72.
[http://dx.doi.org/10.5662/wjm.v4.i2.59] [PMID: 25332906]
[5]
Borel, C.; Antonarakis, S.E. Functional genetic variation of human miRNAs and phenotypic consequences. Mamm. Genome, 2008, 19(7-8), 503-509.
[http://dx.doi.org/10.1007/s00335-008-9137-6] [PMID: 18787897]
[6]
O’Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. ′Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. (Lausanne), 2018, 9, 402.
[http://dx.doi.org/10.3389/fendo.2018.00402] [PMID: 30123182]
[7]
Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell, 2005, 120(1), 15-20.
[http://dx.doi.org/10.1016/j.cell.2004.12.035] [PMID: 15652477]
[8]
Duursma, A.M.; Kedde, M.; Schrier, M.; le Sage, C.; Agami, R. miR-148 targets human DNMT3b protein coding region. RNA, 2008, 14(5), 872-877.
[http://dx.doi.org/10.1261/rna.972008] [PMID: 18367714]
[9]
Yu, S.L.; Chen, H.Y.; Chang, G.C.; Chen, C.Y.; Chen, H.W.; Singh, S.; Cheng, C.L.; Yu, C.J.; Lee, Y.C.; Chen, H.S.; Su, T.J.; Chiang, C.C.; Li, H.N.; Hong, Q.S.; Su, H.Y.; Chen, C.C.; Chen, W.J.; Liu, C.C.; Chan, W.K.; Chen, W.J.; Li, K.C.; Chen, J.J.; Yang, P.C. MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell, 2008, 13(1), 48-57.
[http://dx.doi.org/10.1016/j.ccr.2007.12.008] [PMID: 18167339]
[10]
Duncavage, E.; Goodgame, B.; Sezhiyan, A.; Govindan, R.; Pfeifer, J. Use of microRNA expression levels to predict outcomes in resected stage I non-small cell lung cancer. J. Thorac. Oncol., 2010, 5(11), 1755-1763.
[http://dx.doi.org/10.1097/JTO.0b013e3181f3909d] [PMID: 20975375]
[11]
Zhang, J.; Chong, C.C.; Chen, G.G.; Lai, P.B. A Seven-microRNA expression signature predicts survival in hepatocellular carcinoma. PLoS One, 2015, 10(6): e0128628
[http://dx.doi.org/10.1371/journal.pone.0128628] [PMID: 26046780]
[12]
Ding, B.; Gao, X.; Li, H.; Liu, L.; Hao, X. A novel microRNA signature predicts survival in stomach adenocarcinoma. Oncotarget, 2017, 8(17), 28144-28153.
[http://dx.doi.org/10.18632/oncotarget.15961] [PMID: 28423653]
[13]
Liu, N.; Chen, N.Y.; Cui, R.X.; Li, W.F.; Li, Y.; Wei, R.R.; Zhang, M.Y.; Sun, Y.; Huang, B.J.; Chen, M.; He, Q.M.; Jiang, N.; Chen, L.; Cho, W.C.; Yun, J.P.; Zeng, J.; Liu, L.Z.; Li, L.; Guo, Y.; Wang, H.Y.; Ma, J. Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis. Lancet Oncol., 2012, 13(6), 633-641.
[http://dx.doi.org/10.1016/S1470-2045(12)70102-X] [PMID: 22560814]
[14]
Batista, P.J.; Chang, H.Y. Long noncoding RNAs: cellular address codes in development and disease. Cell, 2013, 152(6), 1298-1307.
[http://dx.doi.org/10.1016/j.cell.2013.02.012] [PMID: 23498938]
[15]
Lin, C.; Yang, L. Long noncoding RNA in cancer: wiring signaling circuitry. Trends Cell Biol., 2018, 28(4), 287-301.
[http://dx.doi.org/10.1016/j.tcb.2017.11.008] [PMID: 29274663]
[16]
Wang, P.; Lu, S.; Mao, H.; Bai, Y.; Ma, T.; Cheng, Z.; Zhang, H.; Jin, Q.; Zhao, J.; Mao, H. Identification of biomarkers for the detection of early stage lung adenocarcinoma by microarray profiling of long noncoding RNAs. Lung Cancer, 2015, 88(2), 147-153.
[http://dx.doi.org/10.1016/j.lungcan.2015.02.009] [PMID: 25758555]
[17]
Zhou, M.; Guo, M.; He, D.; Wang, X.; Cui, Y.; Yang, H.; Hao, D.; Sun, J. A potential signature of eight long non-coding RNAs predicts survival in patients with non-small cell lung cancer. J. Transl. Med., 2015, 13, 231.
[http://dx.doi.org/10.1186/s12967-015-0556-3] [PMID: 26183581]
[18]
Abbas, T.; Dutta, A. p21 in cancer: intricate networks and multiple activities. Nat. Rev. Cancer, 2009, 9(6), 400-414.
[http://dx.doi.org/10.1038/nrc2657] [PMID: 19440234]
[19]
Karimian, A.; Ahmadi, Y.; Yousefi, B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst.), 2016, 42, 63-71.
[http://dx.doi.org/10.1016/j.dnarep.2016.04.008] [PMID: 27156098]
[20]
Dutto, I.; Tillhon, M.; Cazzalini, O.; Stivala, L.A.; Prosperi, E. Biology of the cell cycle inhibitor p21(CDKN1A): molecular mechanisms and relevance in chemical toxicology. Arch. Toxicol., 2015, 89(2), 155-178.
[http://dx.doi.org/10.1007/s00204-014-1430-4] [PMID: 25514883]
[21]
He, X.; Duan, C.; Chen, J.; Ou-Yang, X.; Zhang, Z.; Li, C.; Peng, H. Let-7a elevates p21(WAF1) levels by targeting of NIRF and suppresses the growth of A549 lung cancer cells. FEBS Lett., 2009, 583(21), 3501-3507.
[http://dx.doi.org/10.1016/j.febslet.2009.10.007] [PMID: 19818775]
[22]
Ivanovska, I.; Ball, A.S.; Diaz, R.L.; Magnus, J.F.; Kibukawa, M.; Schelter, J.M.; Kobayashi, S.V.; Lim, L.; Burchard, J.; Jackson, A.L.; Linsley, P.S.; Cleary, M.A. MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Mol. Cell. Biol., 2008, 28(7), 2167-2174.
[http://dx.doi.org/10.1128/MCB.01977-07] [PMID: 18212054]
[23]
Liu, Z.; Sun, M.; Lu, K.; Liu, J.; Zhang, M.; Wu, W.; De, W.; Wang, Z.; Wang, R. The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression. PLoS One, 2013, 8(10): e77293
[http://dx.doi.org/10.1371/journal.pone.0077293] [PMID: 24155936]
[24]
Braun, C.J.; Zhang, X.; Savelyeva, I.; Wolff, S.; Moll, U.M.; Schepeler, T.; Ørntoft, T.F.; Andersen, C.L.; Dobbelstein, M. p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest. Cancer Res., 2008, 68(24), 10094-10104.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-1569] [PMID: 19074875]
[25]
Hu, X.; Feng, Y.; Zhang, D.; Zhao, S.D.; Hu, Z.; Greshock, J.; Zhang, Y.; Yang, L.; Zhong, X.; Wang, L-P.; Jean, S.; Li, C.; Huang, Q.; Katsaros, D.; Montone, K.T.; Tanyi, J.L.; Lu, Y.; Boyd, J.; Nathanson, K.L.; Li, H.; Mills, G.B.; Zhang, L. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell, 2014, 26(3), 344-357.
[http://dx.doi.org/10.1016/j.ccr.2014.07.009] [PMID: 25203321]
[26]
Dimitrova, N.; Zamudio, J.R.; Jong, R.M.; Soukup, D.; Resnick, R.; Sarma, K.; Ward, A.J.; Raj, A.; Lee, J.T.; Sharp, P.A.; Jacks, T. LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Mol. Cell, 2014, 54(5), 777-790.
[http://dx.doi.org/10.1016/j.molcel.2014.04.025] [PMID: 24857549]
[27]
Chen, C.; Lu, Z.; Yang, J.; Hao, W.; Qin, Y.; Wang, H.; Xie, C.; Xie, R. MiR-17-5p promotes cancer cell proliferation and tumorigenesis in nasopharyngeal carcinoma by targeting p21. Cancer Med., 2016, 5(12), 3489-3499.
[http://dx.doi.org/10.1002/cam4.863] [PMID: 27774777]
[28]
Lei, S.T.; Shen, F.; Chen, J.W.; Feng, J.H.; Cai, W.S.; Shen, L.; Hu, Z.W.; Xu, B. MiR-639 promoted cell proliferation and cell cycle in human thyroid cancer by suppressing CDKN1A expression. Biomed. Pharmacother., 2016, 84, 1834-1840.
[http://dx.doi.org/10.1016/j.biopha.2016.10.087] [PMID: 27829546]
[29]
Xu, S.; Huang, H.; Chen, Y.N.; Deng, Y.T.; Zhang, B.; Xiong, X.D.; Yuan, Y.; Zhu, Y.; Huang, H.; Xie, L.; Liu, X. DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21WAF1/CIP1. Cell Cycle, 2016, 15(21), 2920-2930.
[http://dx.doi.org/10.1080/15384101.2016.1224043] [PMID: 27559850]
[30]
Ding, J.; Xie, M.; Lian, Y.; Zhu, Y.; Peng, P.; Wang, J.; Wang, L.; Wang, K. Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2, LSD1 in colorectal cancer. Oncogenesis, 2017, 6(1), e288
[http://dx.doi.org/10.1038/oncsis.2016.84] [PMID: 28112720]
[31]
Liu, Y.W.; Xia, R.; Lu, K.; Xie, M.; Yang, F.; Sun, M.; De, W.; Wang, C.; Ji, G. LincRNAFEZF1-AS1 represses p21 expression to promote gastric cancer proliferation through LSD1-Mediated H3K4me2 demethylation. Mol. Cancer, 2017, 16(1), 39.
[http://dx.doi.org/10.1186/s12943-017-0588-9] [PMID: 28209170]
[32]
Li, J.; Xu, Y.H.; Lu, Y.; Ma, X.P.; Chen, P.; Luo, S.W.; Jia, Z.G.; Liu, Y.; Guo, Y. Identifying differentially expressed genes and small molecule drugs for prostate cancer by a bioinformatics strategy. Asian Pac. J. Cancer Prev., 2013, 14(9), 5281-5286.
[http://dx.doi.org/10.7314/APJCP.2013.14.9.5281] [PMID: 24175814]
[33]
Liu, G.; Yang, D.; Rupaimoole, R.; Pecot, C.V.; Sun, Y.; Mangala, L.S.; Li, X.; Ji, P.; Cogdell, D.; Hu, L.; Wang, Y.; Rodriguez-Aguayo, C.; Lopez-Berestein, G.; Shmulevich, I.; De Cecco, L.; Chen, K.; Mezzanzanica, D.; Xue, F.; Sood, A.K.; Zhang, W. Augmentation of response to chemotherapy by microRNA-506 through regulation of RAD51 in serous ovarian cancers. J. Natl. Cancer Inst., 2015, 107(7), djv108
[http://dx.doi.org/10.1093/jnci/djv108] [PMID: 25995442]
[34]
Wang, X.H.; Lu, Y.; Liang, J.J.; Cao, J.X.; Jin, Y.Q.; An, G.S.; Ni, J.H.; Jia, H.T.; Li, S.Y. MiR-509-3-5p causes aberrant mitosis and anti-proliferative effect by suppression of PLK1 in human lung cancer A549 cells. Biochem. Biophys. Res. Commun., 2016, 478(2), 676-682.
[http://dx.doi.org/10.1016/j.bbrc.2016.08.006] [PMID: 27498003]
[35]
Cao, J.X.; Lu, Y.; Qi, J.J.; An, G.S.; Mao, Z.B.; Jia, H.T.; Li, S.Y.; Ni, J.H. MiR-630 inhibits proliferation by targeting CDC7 kinase, but maintains the apoptotic balance by targeting multiple modulators in human lung cancer A549 cells. Cell Death Dis., 2014, 5, e1426
[http://dx.doi.org/10.1038/cddis.2014.386] [PMID: 25255219]
[36]
Yoon, J.H.; Abdelmohsen, K.; Gorospe, M. Functional interactions among microRNAs and long noncoding RNAs. Semin. Cell Dev. Biol., 2014, 34, 9-14.
[http://dx.doi.org/10.1016/j.semcdb.2014.05.015] [PMID: 24965208]
[37]
Mercer, T.R.; Dinger, M.E.; Mattick, J.S. Long non-coding RNAs: insights into functions. Nat. Rev. Genet., 2009, 10(3), 155-159.
[http://dx.doi.org/10.1038/nrg2521] [PMID: 19188922]
[38]
Du, Z.; Sun, T.; Hacisuleyman, E.; Fei, T.; Wang, X.; Brown, M.; Rinn, J.L.; Lee, M.G.; Chen, Y.; Kantoff, P.W.; Liu, X.S. Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer. Nat. Commun., 2016, 7, 10982.
[http://dx.doi.org/10.1038/ncomms10982] [PMID: 26975529]
[39]
Tsang, F.H.; Au, S.L.; Wei, L.; Fan, D.N.; Lee, J.M.; Wong, C.C.; Ng, I.O.; Wong, C.M. Long non-coding RNA HOTTIP is frequently up-regulated in hepatocellular carcinoma and is targeted by tumour suppressive miR-125b. Liver Int., 2015, 35(5), 1597-1606.
[http://dx.doi.org/10.1111/liv.12746] [PMID: 25424744]
[40]
Han, Y.; Liu, Y.; Zhang, H.; Wang, T.; Diao, R.; Jiang, Z.; Gui, Y.; Cai, Z. Hsa-miR-125b suppresses bladder cancer development by down-regulating oncogene SIRT7 and oncogenic long non-coding RNA MALAT1. FEBS Lett., 2013, 587(23), 3875-3882.
[http://dx.doi.org/10.1016/j.febslet.2013.10.023] [PMID: 24396870]
[41]
Li, C.H.; Chen, Y. Targeting long non-coding RNAs in cancers: progress and prospects. Int. J. Biochem. Cell Biol., 2013, 45(8), 1895-1910.
[http://dx.doi.org/10.1016/j.biocel.2013.05.030] [PMID: 23748105]
[42]
Ning, Q.; Li, Y.; Wang, Z.; Zhou, S.; Sun, H.; Yu, G. The evolution and expression pattern of human overlapping lncRNA and protein-coding gene pairs. Sci. Rep., 2017, 7, 42775.
[http://dx.doi.org/10.1038/srep42775] [PMID: 28344339]


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VOLUME: 20
ISSUE: 10
Year: 2020
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DOI: 10.2174/1568026620666200306102713
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