Abstract
Recently, emerging evidence has suggested that long noncoding RNAs (lncRNAs) have crucial roles in cancer progression. Here, we demonstrated that the lncRNA MIR4435-2HG was highly expressed in lung cancer tissues and correlated with histological grades and lymph node metastasis. Phenotypic analysis indicated that MIR4435-2HG knockdown inhibited lung cancer cell proliferation and invasion in vitro and in vivo. Notably, MIR4435-2HG knockdown suppressed the EMT (epithelial-mesenchymal transition) process and cancer stem cell traits of lung cancer cells. Mechanistically, MIR4435-2HG knockdown decreased the transactivation of β-catenin. MIR4435-2HG interacted with β-catenin and thus prevented its degradation by the proteasome system. Our findings highlight the important roles and mechanisms of MIR4435-2HG in lung cancer progression. High expression of lncRNA MIR4435-2HG correlates with lung cancer progression MIR4435-2HG promotes lung cancer cells proliferation and invasion MIR4435-2HG knockdown suppresses the EMT process and cancer stem cell traits MIR4435-2HG knockdown inhibits the β-catenin signalling.
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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90
Heist RS, Engelman JA (2012) SnapShot: non-small cell lung cancer. Cancer Cell 21:448 e442
Zhang J, Wang J, Xing H, Li Q, Zhao Q, Li J (2016) Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells. Mol Cell Biochem 411:331–340
Gonzalez de Castro D, Clarke PA, Al-Lazikani B, Workman P (2013) Personalized cancer medicine: molecular diagnostics, predictive biomarkers, and drug resistance. Clin Pharmacol Ther 93:252–259
Ulitsky I, Bartel DP (2013) lincRNAs: genomics, evolution, and mechanisms. Cell 154:26–46
Batista PJ, Chang HY (2013) Long noncoding RNAs: cellular address codes in development and disease. Cell 152:1298–1307
Tao H, Zhang JG, Qin RH, Dai C, Shi P, Yang JJ, Deng ZY, Shi KH (2017) LncRNA GAS5 controls cardiac fibroblast activation and fibrosis by targeting miR-21 via PTEN/MMP-2 signaling pathway. Toxicology 386:11–18
Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, Horlings HM, Shah N, Umbricht C, Wang P, Wang Y, Kong B, Langerød A, Børresen-Dale AL, Kim SK, van de Vijver M, Sukumar S, Whitfield ML, Kellis M, Xiong Y, Wong DJ, Chang HY (2011) Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet 43:621–629
Luo M, Jeong M, Sun D, Park HJ, Rodriguez BA, Xia Z, Yang L, Zhang X, Sheng K, Darlington GJ et al (2015) Long non-coding RNAs control hematopoietic stem cell function. Cell Stem Cell 16:426–438
Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S, Abo R, Tabebordbar M, Lee RT, Burge CB, Boyer LA (2013) Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 152:570–583
Arab K, Park YJ, Lindroth AM, Schafer A, Oakes C, Weichenhan D, Lukanova A, Lundin E, Risch A, Meister M et al (2014) Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Mol Cell 55:604–614
Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC, Wang SB, Wang YZ, Yang Y, Yang N, Zhou WP, Yang GS, Sun SH (2014) A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 25:666–681
Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, Yan X, Ye B, Li C, Xia P et al (2015) The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell 16:413–425
Geisler S, Coller J (2013) RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol 14:699–712
Zhu H, Zhang L, Yan S, Li W, Cui J, Zhu M, Xia N, Yang Y, Yuan J, Chen X, Luo J, Chen R, Xing R, Lu Y, Wu N (2017) LncRNA16 is a potential biomarker for diagnosis of early-stage lung cancer that promotes cell proliferation by regulating the cell cycle. Oncotarget 8:7867–7877
Han L, Zhang EB, Yin DD, Kong R, Xu TP, Chen WM, Xia R, Shu YQ, De W (2015) Low expression of long noncoding RNA PANDAR predicts a poor prognosis of non-small cell lung cancer and affects cell apoptosis by regulating Bcl-2. Cell Death Dis 6:e1665
Yang Q, Xu E, Dai J, Liu B, Han Z, Wu J, Zhang S, Peng B, Zhang Y, Jiang Y (2015) A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol 285:79–88
Deng LL, Chi YY, Liu L, Huang NS, Wang L, Wu J (2016) LINC00978 predicts poor prognosis in breast cancer patients. Sci Rep 6:37936
Fu M, Huang Z, Zang X, Pan L, Liang W, Chen J, Qian H, Xu W, Jiang P, Zhang X (2018) Long noncoding RNA LINC00978 promotes cancer growth and acts as a diagnostic biomarker in gastric cancer. Cell Prolif 51. https://doi.org/10.1111/cpr.12425
Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273
Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890
Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751
Li T, Xie J, Shen C, Cheng D, Shi Y, Wu Z, Deng X, Chen H, Shen B, Peng C, Li H, Zhan Q, Zhu Z (2016) Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma. Oncogene 35:1575–1584
Chen X, Han H, Li Y, Zhang Q, Mo K, Chen S (2016) Upregulation of long noncoding RNA HOTTIP promotes metastasis of esophageal squamous cell carcinoma via induction of EMT. Oncotarget 7:84480–84485
Terashima M, Tange S, Ishimura A, Suzuki T (2017) MEG3 long noncoding RNA contributes to the epigenetic regulation of epithelial-mesenchymal transition in lung cancer cell lines. J Biol Chem 292:82–99
Lu W, Zhang H, Niu Y, Wu Y, Sun W, Li H, Kong J, Ding K, Shen HM, Wu H, Xia D, Wu Y (2017) Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p. Mol Cancer 16:118
Zhen T, Dai S, Li H, Yang Y, Kang L, Shi H, Zhang F, Yang D, Cai S, He Y, Liang Y, Han A (2014) MACC1 promotes carcinogenesis of colorectal cancer via beta-catenin signaling pathway. Oncotarget 5:3756–3769
Maftouh M, Belo AI, Avan A, Funel N, Peters GJ, Giovannetti E, Van Die I (2014) Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/beta-catenin signalling in pancreatic adenocarcinoma. Oncotarget 5:5335–5349
Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D, So CW (2010) Beta-catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 18:606–618
Nguyen DX, Chiang AC, Zhang XH, Kim JY, Kris MG, Ladanyi M, Gerald WL, Massague J (2009) WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138:51–62
Fang L, Cai J, Chen B, Wu S, Li R, Xu X, Yang Y, Guan H, Zhu X, Zhang L, Yuan J, Wu J, Li M (2015) Aberrantly expressed miR-582-3p maintains lung cancer stem cell-like traits by activating Wnt/beta-catenin signalling. Nat Commun 6:8640
Su J, Wu S, Wu H, Li L, Guo T (2016) CD44 is functionally crucial for driving lung cancer stem cells metastasis through Wnt/beta-catenin-FoxM1-Twist signaling. Mol Carcinog 55:1962–1973
Authors’ contributions statement
HQ, LC, XW, SM, LLuo and LLing performed the research; JH and FC statistically analysed the experimental data; KL and GZ designed the study and wrote the paper.
Funding
This study was supported by grants from the National Natural Science Foundation of China (81672616 and 81402196) the Guangdong Natural Science Funds for Distinguished Young Scholars, China (2016A030306003), the Science and Technology Program of Guangzhou, China (201710010100), the Guangzhou Municipal University Scientific Research Project (1201610027) and supported by Guangzhou key medical discipline construction project fund.
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Qian, H., Chen, L., Huang, J. et al. The lncRNA MIR4435-2HG promotes lung cancer progression by activating β-catenin signalling. J Mol Med 96, 753–764 (2018). https://doi.org/10.1007/s00109-018-1654-5
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DOI: https://doi.org/10.1007/s00109-018-1654-5