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Long non-coding RNA SMASR inhibits the EMT by negatively regulating TGF-β/Smad signaling pathway in lung cancer

Oncogene volume 40, pages 3578–3592 (2021)Cite this article

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Abstract

TGF-β/Smad signaling pathway plays an important role in EMT during cancer progression. Long non-coding RNAs (lncRNAs) are involved in various behaviors of cancer cells, including EMT. Here, we report a novel lncRNA adjacent to Smad3, named Smad3-associated long non-coding RNA (SMASR). SMASR is downregulated by TGF-β via Smad2/3 in lung cancer cells. Knockdown of SMASR induces EMT and increases the migration and invasion of lung cancer cells. Moreover, knockdown of SMASR promotes the phosphorylation of Smad2/3. Mechanistically, SMASR interacts with Smad2/3 and inhibits the expression of TGFBR1, the TGF-β type I receptor responsible for phosphorylation of Smad2/3, thus leading to inactivation of TGF-β/Smad signaling pathway. Clinically, SMASR is downregulated in lung cancer tissues. Collectively, our findings prove a critical role of SMASR in EMT of lung cancer by forming a negative feedback loop with TGF-β/Smad signaling pathway.

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Fig. 1: SMASR is downregulated by TGF-β in a Smad2/3 dependent manner.
Fig. 2: Knockdown of SMASR induces EMT and promotes cell migration and invasion.
Fig. 3: Knockdown of SMASR promotes Smad3 phosphorylation.
Fig. 4: SMASR regulates TGFBR1 expression.
Fig. 5: SMASR interacts with Smad3 and recruits Smad3 to TGFBR1 promoter.
Fig. 6: SMASR is downregulated in human lung cancer and is associated with poor prognosis.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  2. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119:1420–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.

    CAS  PubMed  Google Scholar 

  4. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20:69–84.

    CAS  PubMed  Google Scholar 

  5. Hao Y, Baker D, Ten Dijke P. TGF-beta-mediated epithelial-mesenchymal transition and cancer metastasis. Int J Mol Sci. 2019;20:2767.

    PubMed Central  Google Scholar 

  6. Singh M, Yelle N, Venugopal C, Singh SK. EMT: mechanisms and therapeutic implications. Pharm Ther. 2018;182:80–94.

    CAS  Google Scholar 

  7. Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res. 2013;19:279–90.

    CAS  PubMed  Google Scholar 

  8. Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19:156–72.

    CAS  PubMed  Google Scholar 

  9. Miettinen PJ, Ebner R, Lopez AR, Derynck R. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol. 1994;127:2021–36.

    CAS  PubMed  Google Scholar 

  10. Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest. 2003;112:1486–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 2005;16:1987–2002.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10:415–24.

    CAS  PubMed  Google Scholar 

  13. Wang Z, Yang B, Zhang M, Guo W, Wu Z, Wang Y, et al. lncRNA epigenetic landscape analysis identifies EPIC1 as an oncogenic lncRNA that interacts with MYC and promotes cell-cycle progression in cancer. Cancer Cell. 2018;33:706–20.e709.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Huang L, Wang Y, Chen J, Wang Y, Zhao Y, Wang Y, et al. Long noncoding RNA PCAT1, a novel serum-based biomarker, enhances cell growth by sponging miR-326 in oesophageal squamous cell carcinoma. Cell Death Dis. 2019;10:513.

    PubMed  PubMed Central  Google Scholar 

  15. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Yang F, Huo XS, Yuan SX, Zhang L, Zhou WP, Wang F, et al. Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol Cell. 2013;49:1083–96.

    CAS  PubMed  Google Scholar 

  17. Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene. 2009;28:195–208.

    CAS  PubMed  Google Scholar 

  18. Postepska-Igielska A, Giwojna A, Gasri-Plotnitsky L, Schmitt N, Dold A, Ginsberg D, et al. LncRNA Khps1 regulates expression of the proto-oncogene SPHK1 via triplex-mediated changes in chromatin structure. Mol Cell. 2015;60:626–36.

    CAS  PubMed  Google Scholar 

  19. Sang LJ, Ju HQ, Liu GP, Tian T, Ma GL, Lu YX, et al. LncRNA CamK-A regulates Ca(2+)-signaling-mediated tumor microenvironment remodeling. Mol Cell. 2018;72:71–83 e77.

    CAS  PubMed  Google Scholar 

  20. Chen F, Chen J, Yang L, Liu J, Zhang X, Zhang Y, et al. Extracellular vesicle-packaged HIF-1alpha-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells. Nat Cell Biol. 2019;21:498–510.

    CAS  PubMed  Google Scholar 

  21. Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell. 2016;29:653–68.

    CAS  PubMed  Google Scholar 

  22. Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25:666–81.

    CAS  PubMed  Google Scholar 

  23. Wu N, Jiang M, Liu H, Chu Y, Wang D, Cao J. LINC00941 promotes CRC metastasis through preventing SMAD4 protein degradation and activating the TGF-beta/SMAD2/3 signaling pathway. Cell Death Differ. 2021;28:219–32.

    CAS  PubMed  Google Scholar 

  24. Sakai S, Ohhata T, Kitagawa K, Uchida C, Aoshima T, Niida H, et al. Long noncoding RNA ELIT-1 acts as a Smad3 cofactor to facilitate TGFbeta/Smad signaling and promote epithelial-mesenchymal transition. Cancer Res. 2019;79:2821–38.

    CAS  PubMed  Google Scholar 

  25. Wang YQ, Jiang DM, Hu SS, Zhao L, Wang L, Yang MH, et al. SATB2-AS1 suppresses colorectal carcinoma aggressiveness by inhibiting SATB2-dependent snail transcription and epithelial-mesenchymal transition. Cancer Res. 2019;79:3542–56.

    CAS  PubMed  Google Scholar 

  26. Arab K, Park YJ, Lindroth AM, Schafer A, Oakes C, Weichenhan D, et al. Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Mol Cell. 2014;55:604–14.

    CAS  PubMed  Google Scholar 

  27. Dimitrova N, Zamudio JR, Jong RM, Soukup D, Resnick R, Sarma K, et al. LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Mol Cell. 2014;54:777–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang L, Zhao Y, Bao X, Zhu X, Kwok YK, Sun K, et al. LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration. Cell Res. 2015;25:335–50.

    PubMed  PubMed Central  Google Scholar 

  29. Miao H, Wang L, Zhan H, Dai J, Chang Y, Wu F, et al. A long noncoding RNA distributed in both nucleus and cytoplasm operates in the PYCARD-regulated apoptosis by coordinating the epigenetic and translational regulation. PLoS Genet. 2019;15:e1008144.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, et al. Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature. 2012;491:454–7.

    CAS  PubMed  Google Scholar 

  31. Kopp F, Mendell JT. Functional classification and experimental dissection of long noncoding RNAs. Cell. 2018;172:393–407.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen LL. Linking long noncoding RNA localization and function. Trends Biochem Sci. 2016;41:761–72.

    CAS  PubMed  Google Scholar 

  33. Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, et al. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 2010;142:409–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Schmitt AM, Garcia JT, Hung T, Flynn RA, Shen Y, Qu K, et al. An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet. 2016;48:1370–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet. 2011;43:621–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang L, Park HJ, Dasari S, Wang S, Kocher JP, Li W. CPAT: coding-potential assessment tool using an alignment-free logistic regression model. Nucleic Acids Res. 2013;41:e74.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Yeung KT, Yang J. Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol. 2017;11:28–39.

    PubMed  Google Scholar 

  38. Tseng YY, Moriarity BS, Gong W, Akiyama R, Tiwari A, Kawakami H, et al. PVT1 dependence in cancer with MYC copy-number increase. Nature. 2014;512:82–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Acha-Sagredo A, Uko B, Pantazi P, Bediaga NG, Moschandrea C, Rainbow L, et al. Long non-coding RNA dysregulation is a frequent event in non-small cell lung carcinoma pathogenesis. Br J Cancer. 2020;122:1050–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Grelet S, Link LA, Howley B, Obellianne C, Palanisamy V, Gangaraju VK, et al. A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nat Cell Biol. 2017;19:1105–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F, et al. TGF-beta-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12. Clin Cancer Res. 2014;20:1531–41.

    CAS  PubMed  Google Scholar 

  42. Hu WL, Jin L, Xu A, Wang YF, Thorne RF, Zhang XD, et al. GUARDIN is a p53-responsive long non-coding RNA that is essential for genomic stability. Nat Cell Biol. 2018;20:492–502.

    PubMed  Google Scholar 

  43. Liu B, Sun L, Liu Q, Gong C, Yao Y, Lv X, et al. A cytoplasmic NF-kappaB interacting long noncoding RNA blocks IkappaB phosphorylation and suppresses breast cancer metastasis. Cancer Cell. 2015;27:370–81.

    CAS  PubMed  Google Scholar 

  44. Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell. 2015;16:413–25.

    CAS  PubMed  Google Scholar 

  45. Trimarchi T, Bilal E, Ntziachristos P, Fabbri G, Dalla-Favera R, Tsirigos A, et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell. 2014;158:593–606.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29:452–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Rodriguez-Mateo C, Torres B, Gutierrez G, Pintor-Toro JA. Downregulation of Lnc-Spry1 mediates TGF-beta-induced epithelial-mesenchymal transition by transcriptional and posttranscriptional regulatory mechanisms. Cell Death Differ. 2017;24:785–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Rossi M, Bucci G, Rizzotto D, Bordo D, Marzi MJ, Puppo M, et al. LncRNA EPR controls epithelial proliferation by coordinating Cdkn1a transcription and mRNA decay response to TGF-beta. Nat Commun. 2019;10:1969.

    PubMed  PubMed Central  Google Scholar 

  49. Xia M, Liu J, Liu S, Chen K, Lin H, Jiang M, et al. Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity. Nat Commun. 2017;8:15818.

    PubMed  PubMed Central  Google Scholar 

  50. Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22:571–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, et al. MEG3 long noncoding RNA regulates the TGF-beta pathway genes through formation of RNA-DNA triplex structures. Nat Commun. 2015;6:7743.

    CAS  PubMed  Google Scholar 

  52. Wang P, Luo ML, Song E, Zhou Z, Ma T, Wang J. Long noncoding RNA lnc-TSI inhibits renal fibrogenesis by negatively regulating the TGF-beta/Smad3 pathway. Sci Transl Med. 2018;10:eaat2039.

    PubMed  Google Scholar 

  53. Zhang K, Han X, Zhang Z, Zheng L, Hu Z, Yao Q, et al. The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFbeta and Notch pathways. Nat Commun. 2017;8:144.

    PubMed  PubMed Central  Google Scholar 

  54. Wang P, Xue Y, Han Y, Lin L, Wu C, Xu S, et al. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science. 2014;344:310–3.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Basic Research Program of China (973 Program) (2015CB553906), the National Natural Science Foundation of China (81988101 and 81830086), the third round of public welfare development and reform pilot projects of Beijing Municipal Medical Research Institutes (Beijing Medical Research Institute, 2019-1), and the Beijing Municipal Commission of Health and Family Planning Project (PXM2018_026279_000005). The results shown here are part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

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  1. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China

    Lele Xu, Wenzhong Liu, Tongtong Li, Yu Wang, Lijie Huang, Xuefeng Liu & Qimin Zhan

  2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, China

    Yuying Hu, Yan Wang & Qimin Zhan

  3. Liaoning Key Laboratory of Proteomics, Dalian Medical University, Dalian, China

    Shujuan Shao

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Xu, L., Liu, W., Li, T. et al. Long non-coding RNA SMASR inhibits the EMT by negatively regulating TGF-β/Smad signaling pathway in lung cancer. Oncogene 40, 3578–3592 (2021). https://doi.org/10.1038/s41388-021-01760-2

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