lncRNAs as Potential Targets in Small Cell Lung Cancer: MYC -dependent Regulation

Author(s): Onur Tokgun*, Pervin E. Tokgun, Kubilay Inci, Hakan Akca

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 17 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Small Cell Lung Cancer (SCLC) is a highly aggressive malignancy. MYC family oncogenes are amplified and overexpressed in 20% of SCLCs, showing that MYC oncogenes and MYC regulated genes are strong candidates as therapeutic targets for SCLC. c-MYC plays a fundamental role in cancer stem cell properties and malignant transformation. Several targets have been identified by the activation/repression of MYC. Deregulated expression levels of lncRNAs have also been observed in many cancers.

Objective: The aim of the present study is to investigate the lncRNA profiles which depend on MYC expression levels in SCLC.

Methods: Firstly, we constructed lentiviral vectors for MYC overexpression/inhibition. MYC expression is suppressed by lentiviral shRNA vector in MYC amplified H82 and N417 cells, and overexpressed by lentiviral inducible overexpression vector in MYC non-amplified H345 cells. LncRNA cDNA is transcribed from total RNA samples, and 91 lncRNAs are evaluated by qRT-PCR.

Results: We observed that N417, H82 and H345 cells require MYC for their growth. Besides, MYC is not only found to regulate the expressions of genes related to invasion, stem cell properties, apoptosis and cell cycle (p21, Bcl2, cyclinD1, Sox2, Aldh1a1, and N-Cadherin), but also found to regulate lncRNAs. With this respect, expressions of AK23948, ANRIL, E2F4AS, GAS5, MEG3, H19, L1PA16, SFMBT2, ZEB2NAT, HOTAIR, Sox2OT, PVT1, and BC200 were observed to be in parallel with MYC expression, whereas expressions of Malat1, PTENP1, Neat1, UCA1, SNHG3, and SNHG6 were inversely correlated.

Conclusion: Targeting MYC-regulated genes as a therapeutic strategy can be important for SCLC therapy. This study indicated the importance of identifying MYC-regulated lncRNAs and that these can be utilized to develop a therapeutic strategy for SCLC.

Keywords: SCLC, MYC , lncRNA, inhibition, overexpression, lentiviral vector.

[1]
Gazdar, A.F.; Bunn, P.A.; Minna, J.D. Small-cell lung cancer: What we know, what we need to know and the path forward. Nat. Rev. Cancer, 2017, 17(12), 725-737.
[http://dx.doi.org/10.1038/nrc.2017.87] [PMID: 29077690]
[2]
Wang, X.D.; Hu, R.; Ding, Q.; Savage, T.K.; Huffman, K.E.; Williams, N.; Cobb, M.H.; Minna, J.D.; Johnson, J.E.; Yu, Y. Subtypespecific secretomic characterization of pulmonary neuroendocrine tumor cells. Nat. Commun., 2019, 10(1), 3201.
[http://dx.doi.org/10.1038/s41467-019-11153-5] [PMID: 31324758]
[3]
Kim, K.B.; Dunn, C.T.; Park, K.S. Recent progress in mapping the emerging landscape of the small-cell lung cancer genome. Exp. Mol. Med., 2019, 51(12), 1-13.
[http://dx.doi.org/10.1038/s12276-019-0349-5] [PMID: 31827074]
[4]
Sundaresan, V.; Lin, V.T.; Liang, F.; Kaye, F.J.; Kawabata-Iwakawa, R.; Shiraishi, K.; Kohno, T.; Yokota, J.; Zhou, L. Significantly mutated genes and regulatory pathways in SCLC-a metaanalysis. Cancer Genet., 2017, 216-217, 20-28.
[http://dx.doi.org/10.1016/j.cancergen.2017.05.003] [PMID: 29025592]
[5]
Yang, S.; Zhang, Z.; Wang, Q. Emerging therapies for small cell lung cancer. J. Hematol. Oncol., 2019, 12(1), 47.
[6]
Brägelmann, J.; Böhm, S.; Guthrie, M.R.; Mollaoglu, G.; Oliver, T.G.; Sos, M.L. Family matters: How MYC family oncogenes impact small cell lung cancer. Cell Cycle, 2017, 16(16), 1489-1498.
[7]
Zhang, W.; Girard, L.; Zhang, Y.A.; Haruki, T.; Papari-Zareei, M.; Stastny, V.; Ghayee, H.K.; Pacak, K.; Oliver, T.G.; Minna, J.D.; Gazdar, A.F. Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl. Lung Cancer Res., 2018, 7(1), 32-49.
[http://dx.doi.org/10.21037/tlcr.2018.02.02] [PMID: 29535911]
[8]
Stinchcombe, T.E. Current treatments for surgically resectable, limited-stage, and extensive-stage small cell lung cancer. Oncologist, 2017, 22(12), 1510-1517.
[http://dx.doi.org/10.1634/theoncologist.2017-0204] [PMID: 28778960]
[9]
Anastasiadou, E.; Jacob, L.S.; Slack, F.J. Non-coding RNA networks in cancer. Nat. Rev. Cancer, 2018, 18(1), 5-18.
[http://dx.doi.org/10.1038/nrc.2017.99] [PMID: 29170536]
[10]
Kim, D.W.; Kim, K.C.; Kim, K.B.; Dunn, C.T.; Park, K.S. Transcriptional deregulation underlying the pathogenesis of small cell lung cancer. Transl. Lung Cancer Res., 2018, 7(1), 4-20.
[http://dx.doi.org/10.21037/tlcr.2017.10.07] [PMID: 29535909]
[11]
Codony-Servat, J.; Verlicchi, A.; Rosell, R. Cancer stem cells in small cell lung cancer. Transl. Lung Cancer Res., 2016, 5(1), 16-25.
[PMID: 26958490]
[12]
Weiss, G.J.; Byron, S.A.; Aldrich, J.; Sangal, A.; Barilla, H.; Kiefer, J.A.; Carpten, J.D.; Craig, D.W.; Whitsett, T.G. A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy. PLoS One, 2017, 12(6)e0179170
[13]
Yang, G.; Lu, X.; Yuan, L. LncRNA: A link between RNA and cancer. Biochim. Biophys. Acta, 2014, 1839(11), 1097-1109.
[http://dx.doi.org/10.1016/j.bbagrm.2014.08.012] [PMID: 25159663]
[14]
Yoshida, G.J. Correction to: Emerging roles of MYC in stem cell biology and novel tumor therapies. J. Exp. Clin. Cancer Res., 2018, 37(1), 285.
[http://dx.doi.org/10.1186/s13046-018-0964-3] [PMID: 30477547]
[15]
Yao, R.W.; Wang, Y.; Chen, L.L. Cellular functions of long noncoding RNAs. Nat. Cell Biol., 2019, 21(5), 542-551.
[http://dx.doi.org/10.1038/s41556-019-0311-8] [PMID: 31048766]
[16]
Yousefi, H.; Maheronnaghsh, M.; Molaei, F.; Mashouri, L.; Reza Aref, A.; Momeny, M.; Alahari, S.K. Long noncoding RNAs and exosomal lncRNAs: Classification, and mechanisms in breast cancer metastasis and drug resistance. Oncogene, 2019, 39(5), 953-974.
[PMID: 31601996]
[17]
Bhan, A.; Soleimani, M.; Mandal, S.S. Long noncoding RNA and cancer: A new paradigm. Cancer Res., 2017, 17(15), 3965-3981.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2634]
[18]
Gou, Q.; Wu, K.; Zhou, J.K.; Xie, Y.; Liu, L.; Peng, Y. Profiling and bioinformatic analysis of circular RNA expression regulated by c-MYC. Oncotarget, 2017, 8(42), 71587-71596.
[http://dx.doi.org/10.18632/oncotarget.17788] [PMID: 29069731]
[19]
Tokgun, P.E.; Tokgun, O.; Kurt, S.; Tomatir, A.G.; Akca, H. MYC-driven regulation of long non-coding RNA profiles in breast cancer cells. Gene, 2019, 714143955
[http://dx.doi.org/10.1016/j.gene.2019.143955] [PMID: 31326549]
[20]
Wang, K.C.; Chang, H.Y. Molecular mechanisms of long noncoding RNAs. Mol. Cell, 2011, 43(6), 904-914.
[http://dx.doi.org/10.1016/j.molcel.2011.08.018] [PMID: 21925379]
[21]
Botti, G.; Marra, L.; Malzone, M.G.; Anniciello, A.; Botti, C.; Franco, R.; Cantile, M. LncRNA HOTAIR as prognostic circulating marker and potential therapeutic target in patients with tumor diseases. Curr. Drug Targets, 2017, 18(1), 27-34.
[http://dx.doi.org/10.2174/1389450117666151209122950] [PMID: 26648066]
[22]
Nai, Y.; Pan, C.; Hu, X.; Ma, Y. LncRNA LUCAT1 contributes to cell proliferation and migration in human pancreatic ductal adenocarcinoma via sponging miR-539. Cancer Med., 2020, 9(2), 757-767.
[PMID: 31789465]
[23]
Unfried, J.P.; Serrano, G.; Suárez, B.; Sangro, P.; Ferretti, V.; Prior, C.; Boix, L.; Bruix, J.; Sangro, B.; Segura, V.; Fortes, P. Identification of coding and long noncoding RNAs differentially expressed in tumors and preferentially expressed in healthy tissues. Cancer Res., 2019, 79(20), 5167-5180.
[http://dx.doi.org/10.1158/0008-5472.CAN-19-0400] [PMID: 31387921]
[24]
Lin, Y.; Leng, Q.; Zhan, M.; Jiang, F. A plasma long noncoding RNA signature for early detection of lung cancer. Transl. Oncol., 2018, 11(5), 1225-1231.
[http://dx.doi.org/10.1016/j.tranon.2018.07.016] [PMID: 30098474]
[25]
Li, T.T.; He, R.Q.; Ma, J.; Li, Z.Y.; Hu, X.H.; Chen, G. Long noncoding RNAs in small cell lung cancer: A potential opening to combat the disease.(Review). Oncol. Rep., 2018, 40(4), 1831-1842.
[http://dx.doi.org/10.3892/or.2018.6635] [PMID: 30106447]
[26]
Ghafouri-Fard, S.; Shoorei, H.; Branicki, W.; Taheri, M. Non-coding RNA profile in lung cancer. Exp. Mol. Pathol., 2020, 114104411
[http://dx.doi.org/10.1016/j.yexmp.2020.104411] [PMID: 32112788]
[27]
Tokgun, O.; Fiorentino, F.P.; Tokgun, P.E.; Yokota, J.; Akca, H. Design of a lentiviral vector for the inducible expression of MYC: A new strategy for construction approach. Mol. Biotechnol., 2017, 59(6), 200-206.
[http://dx.doi.org/10.1007/s12033-017-0006-y] [PMID: 28447263]
[28]
Fiorentino, F.P.; Tokgün, E.; Solé-Sánchez, S.; Giampaolo, S.; Tokgün, O.; Jauset, T.; Kohno, T.; Perucho, M.; Soucek, L.; Yokota, J. Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation. Oncotarget, 2016, 7(21), 31014-31028.
[http://dx.doi.org/10.18632/oncotarget.8826] [PMID: 27105536]
[29]
Hamilton, G.; Rath, B. Combination chemotherapy for relapsed small-cell lung cancer- perspective on mechanisms of chemoresistance. Transl. Cancer Res., 2016, 5, 1255-1261.
[http://dx.doi.org/10.21037/tcr.2016.11.51]
[30]
Kim, Y.H.; Girard, L.; Giacomini, C.P.; Wang, P.; Hernandez-Boussard, T.; Tibshirani, R.; Minna, J.D.; Pollack, J.R. Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification. Oncogene, 2006, 25(1), 130-138.
[http://dx.doi.org/10.1038/sj.onc.1208997] [PMID: 16116477]
[31]
Carabet, L.A.; Rennie, P.S.; Cherkasov, A. Therapeutic Inhibition of MYC in Cancer. Structural bases and computer-aided drug discovery approaches. Int. J. Mol. Sci., 2018, 20(1)E120
[http://dx.doi.org/10.3390/ijms20010120] [PMID: 30597997]
[32]
Li, Y.; Casey, S.C.; Felsher, D.W. Inactivation of MYC reverses tumorigenesis. J. Intern. Med., 2014, 276(1), 52-60.
[http://dx.doi.org/10.1111/joim.12237] [PMID: 24645771]
[33]
Dang, C.V. MYC on the path to cancer. Cell, 2012, 149(1), 22-35.
[http://dx.doi.org/10.1016/j.cell.2012.03.003] [PMID: 22464321]
[34]
Gabay, M.; Li, Y.; Felsher, D.W. MYC activation is a hallmark of cancer initiation and maintenance. Cold Spring Harb. Perspect. Med., 2014, 4(6)a014241
[http://dx.doi.org/10.1101/cshperspect.a014241] [PMID: 24890832]
[35]
Barsyte-Lovejoy, D.; Lau, S.K.; Boutros, P.C.; Khosravi, F.; Jurisica, I.; Andrulis, I.L.; Tsao, M.S.; Penn, L.Z. The c-MYC oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res., 2006, 66(10), 5330-5337.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0037] [PMID: 16707459]
[36]
Ma, M.Z.; Li, C.X.; Zhang, Y.; Weng, M.Z.; Zhang, M.D.; Qin, Y.Y.; Gong, W.; Quan, Z.W. Long non-coding RNA HOTAIR, a c-MYC activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. Mol. Cancer, 2014, 13, 156.
[http://dx.doi.org/10.1186/1476-4598-13-156] [PMID: 24953832]
[37]
Kim, T.; Cui, R.; Jeon, Y.J.; Fadda, P.; Alder, H.; Croce, C.M. MYC-repressed long noncoding RNAs antagonize MYC-induced cell proliferation and cell cycle progression. Oncotarget, 2015, 6(22), 18780-18789.
[http://dx.doi.org/10.18632/oncotarget.3909] [PMID: 26003165]
[38]
Wiese, K.E.; Walz, S.; von Eyss, B.; Wolf, E.; Athineos, D.; Sansom, O.; Eilers, M. The role of MIZ-1 in MYC-dependent tumorigenesis. Cold Spring Harb. Perspect. Med., 2013, 3(12)a014290
[http://dx.doi.org/10.1101/cshperspect.a014290] [PMID: 24296348]
[39]
Guan, H.; Mei, Y.; Mi, Y.; Li, C.; Sun, X.; Zhao, X.; Liu, J.; Cao, W.; Li, Y.; Wang, Y. Downregulation of lncRNA ANRIL suppresses growth and metastasis in human osteosarcoma cells. OncoTargets Ther., 2018, 11, 4893-4899.
[http://dx.doi.org/10.2147/OTT.S170293] [PMID: 30147340]
[40]
Zhang, K.; Li, Y.; Qu, L.; Ma, X.; Zhao, H.; Tang, Y. Long noncoding RNA Sox2 overlapping transcript (SOX2OT) promotes non-small-cell lung cancer migration and invasion via sponging microRNA 132 (miR-132). OncoTargets Ther., 2018, 11, 5269-5278.
[http://dx.doi.org/10.2147/OTT.S168654] [PMID: 30214232]
[41]
Li, Z.; Yan, M.; Yu, Y.; Wang, Y.; Lei, G.; Pan, Y.; Li, N.; Gobin, R.; Yu, J. LncRNA H19 promotes the committed differentiation of stem cells from apical papilla via miR-141/SPAG9 pathway. Cell Death Dis., 2019, 10(2), 130.
[http://dx.doi.org/10.1038/s41419-019-1337-3] [PMID: 30755596]
[42]
Wang, A.H.; Tan, P.; Zhuang, Y.; Zhang, X.T.; Yu, Z.B.; Li, L.N. Down-regulation of long non-coding RNA HOTAIR inhibits invasion and migration of oesophageal cancer cells via up-regulation of microRNA-204. J. Cell. Mol. Med., 2019, 23(10), 6595-6610.
[http://dx.doi.org/10.1111/jcmm.14502] [PMID: 31389660]
[43]
Zhang, X.; Wu, N.; Wang, J.; Li, Z. LncRNA MEG3 inhibits cell proliferation and induces apoptosis in laryngeal cancer via miR-23a/APAF-1 axis. J. Cell. Mol. Med., 2019, 23(10), 6708-6719.
[http://dx.doi.org/10.1111/jcmm.14549] [PMID: 31328388]
[44]
Du, P.; Hu, C.; Qin, Y.; Zhao, J.; Patel, R.; Fu, Y.; Zhu, M.; Zhang, W.; Huang, G. LncRNA PVT1 mediates antiapoptosis and 5-fluorouracil resistance via increasing Bcl2 expression in gastric cancer. J. Oncol., 2019, 20199325407
[http://dx.doi.org/10.1155/2019/9325407] [PMID: 31205469]
[45]
Ji, Q.; Zhang, L.; Liu, X.; Zhou, L.; Wang, W.; Han, Z.; Sui, H.; Tang, Y.; Wang, Y.; Liu, N.; Ren, J.; Hou, F.; Li, Q. Long non-coding RNA MALAT1 promotes tumour growth and metastasis in colorectal cancer through binding to SFPQ and releasing oncogene PTBP2 from SFPQ/PTBP2 complex. Br. J. Cancer, 2014, 111(4), 736-748.
[http://dx.doi.org/10.1038/bjc.2014.383] [PMID: 25025966]
[46]
Xu, S.; Sui, S.; Zhang, J.; Bai, N.; Shi, Q.; Zhang, G.; Gao, S.; You, Z.; Zhan, C.; Liu, F.; Pang, D. Downregulation of long noncoding RNA MALAT1 induces epithelial-to-mesenchymal transition via the PI3K-AKT pathway in breast cancer. Int. J. Clin. Exp. Pathol., 2015, 8(5), 4881-4891.
[PMID: 26191181]
[47]
Liu, L.; Wang, H.J.; Meng, T.; Lei, C.; Yang, X.H.; Wang, Q.S.; Jin, B.; Zhu, J.F. lncRNA GAS5 inhibits cell migration and invasion and promotes autophagy by targeting miR-222-3p via the GAS5/PTEN-signaling pathway in CRC. Mol. Ther. Nucleic Acids, 2019, 17, 644-656.
[http://dx.doi.org/10.1016/j.omtn.2019.06.009] [PMID: 31400607]
[48]
Lv, P.; Qiu, X.; Gu, Y.; Yang, X.; Xu, X.; Yang, Y. Long non-coding RNA SNHG6 enhances cell proliferation, migration and invasion by regulating miR-26a-5p/MAPK6 in breast cancer. Biomed. Pharmacother., 2019, 110, 294-301.
[http://dx.doi.org/10.1016/j.biopha.2018.11.016] [PMID: 30522015]
[49]
Xuan, Y.; Wang, Y. Long non-coding RNA SNHG3 promotes progression of gastric cancer by regulating neighboring MED18 gene methylation. Cell Death Dis., 2019, 10(10), 694.
[http://dx.doi.org/10.1038/s41419-019-1940-3] [PMID: 31534128]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 17
Year: 2020
Page: [2074 - 2081]
Pages: 8
DOI: 10.2174/1871520620666200721130700
Price: $65

Article Metrics

PDF: 31
HTML: 3
EPUB: 1
PRC: 1