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SP1-activated long noncoding RNA lncRNA GCMA functions as a competing endogenous RNA to promote tumor metastasis by sponging miR-124 and miR-34a in gastric cancer

A Correction to this article was published on 10 September 2020

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Abstract

Long noncoding RNAs (lncRNAs) were demonstrated to play important roles in gene regulation and cancer progression. However, the functional roles of lncRNAs and the detailed mechanisms underlying gastric cancer (GC) progression remain largely unclear. Here, we identified a novel cancer-related lncRNA, termed lncRNA GCMA (Gastric Cancer metastasis-associated lncRNA), which was upregulated in GC tissues with lymph node metastasis (LNM) compared with tissues without LNM. High expression of GCMA was significantly associated with poor prognosis of patients with GC. Luciferase assays, bioinformatics analyses and chromatin immunoprecipitation (ChIP) assays indicated that SP1 transcription factor directly bound to the GCMA promoter region and activated its transcription. Functionally, upregulation of GCMA dramatically promoted GC cells proliferation, migration and invasion in vitro, whereas knockdown of GCMA elicited the opposite function. Consistently, stable knockdown of GCMA inhibited tumor proliferation, invasion and metastasis in vivo. Mechanistically, by using bioinformatics analyses, RNA binding protein immunoprecipitation (RIP) assays, luciferase assays and western-blot assays, GCMA was demonstrated to function as a competing endogenous RNA (ceRNA) via competitively absorbing miR-124 and miR-34a to upregulate slug and snail, thereby induced epithelial-mesenchymal transition (EMT) and GC cell metastasis in vitro and in vivo. Collectively, these results demonstrate that GCMA functions as an oncogenic lncRNA that may serve as a potential prognostic biomarker for GC and shed new lights on targeted therapy of GC in the future.

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Fig. 1: Relative expression of GCMA in GC tissues and cell lines, its subcellular location, stability and clinical significance.
Fig. 2: SP1-activated GCMA transcription in GC cells.
Fig. 3: GCMA promotes GC cell migration, invasion and growth in vitro.
Fig. 4: GCMA promotes GC growth, invasion, and metastasis in vivo.
Fig. 5: GCMA functions as a ceRNA for miR-124 and miR-34a.
Fig. 6: GCMA promotes GC progression through a ceRNA pattern in vitro and in vivo.
Fig. 7: GCMA acts as a ceRNA to promote EMT in GC.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    PubMed  Google Scholar 

  2. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9:274–84.

    Article  CAS  Google Scholar 

  3. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127:679–95.

    Article  CAS  Google Scholar 

  4. McLean MH, El-Omar EM. Genetics of gastric cancer. Nat Rev Gastroenterol Hepatol. 2014;11:664–74.

    Article  CAS  Google Scholar 

  5. Wapinski O, Chang HY. Long noncoding RNAs and human disease. Trends Cell Biol. 2011;21:354–61.

    Article  CAS  Google Scholar 

  6. Gibb EA, Brown CJ, Lam WL. The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011;10:38.

    Article  CAS  Google Scholar 

  7. Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat. Rev. Genet. 2009;10:155–9.

    Article  CAS  Google Scholar 

  8. Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011;146:353–8.

    Article  CAS  Google Scholar 

  9. Thomson DW, Dinger ME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet. 2016;17:272–83.

    Article  CAS  Google Scholar 

  10. Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L, et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell. 2013;52:101–12.

    Article  CAS  Google Scholar 

  11. Gao H, Song X, Kang T, Yan B, Feng L, Gao L, et al. Long noncoding RNA CRNDE functions as a competing endogenous RNA to promote metastasis and oxaliplatin resistance by sponging miR-136 in colorectal cancer. Onco Targets Ther. 2017;10:205–16.

    Article  CAS  Google Scholar 

  12. Hu X, Lin J, Jiang M, He X, Wang K, Wang W, et al. HIF-1alpha promotes the metastasis of esophageal squamous cell carcinoma by targeting SP1. J Cancer. 2020;11:229–40.

    Article  CAS  Google Scholar 

  13. Chu PC, Lin PC, Wu HY, Lin KT, Wu C, Bekaii-Saab T, et al. Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway. Oncogene. 2018;37:3440–55.

    Article  CAS  Google Scholar 

  14. Qian Y, Yao W, Yang T, Yang Y, Liu Y, Shen Q, et al. aPKC-iota/P-Sp1/Snail signaling induces epithelial-mesenchymal transition and immunosuppression in cholangiocarcinoma. Hepatology. 2017;66:1165–82.

    Article  CAS  Google Scholar 

  15. Kim WY, Jang JY, Jeon YK, Chung DH, Kim YG, Kim CW. Syntenin increases the invasiveness of small cell lung cancer cells by activating p38, AKT, focal adhesion kinase and SP1. Exp Mol Med. 2014;46:e90.

    Article  CAS  Google Scholar 

  16. Schirle NT, Sheu-Gruttadauria J, MacRae IJ. Structural basis for microRNA targeting. Science. 2014;346:608–13.

    Article  CAS  Google Scholar 

  17. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13:97–110.

    Article  Google Scholar 

  18. Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16:488–94.

    Article  CAS  Google Scholar 

  19. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003;116:499–511.

    Article  CAS  Google Scholar 

  20. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83.

    Article  CAS  Google Scholar 

  21. Fang XY, Pan HF, Leng RX, Ye DQ. Long noncoding RNAs: novel insights into gastric cancer. Cancer Lett. 2015;356:357–66.

    Article  CAS  Google Scholar 

  22. Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15:7–21.

    Article  CAS  Google Scholar 

  23. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol cell. 2011;43:904–14.

    Article  CAS  Google Scholar 

  24. Zhang K, Shi ZM, Chang YN, Hu ZM, Qi HX, Hong W. The ways of action of long non-coding RNAs in cytoplasm and nucleus. Gene. 2014;547:1–9.

    Article  CAS  Google Scholar 

  25. Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev. 2009;23:1494–504.

    Article  CAS  Google Scholar 

  26. Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, et al. lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/beta-catenin signaling. Nat Med. 2017;23:1331–41.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. Song YX, Sun JX, Zhao JH, Yang YC, Shi JX, Wu ZH, et al. Non-coding RNAs participate in the regulatory network of CLDN4 via ceRNA mediated miRNA evasion. Nat Commun. 2017;8:289.

    Article  Google Scholar 

  29. Murray-Stewart T, Sierra JC, Piazuelo MB, Mera RM, Chaturvedi R, Bravo LE, et al. Epigenetic silencing of miR-124 prevents spermine oxidase regulation: implications for Helicobacter pylori-induced gastric cancer. Oncogene. 2016;35:5480–8.

    Article  CAS  Google Scholar 

  30. Jang E, Kim E, Son HY, Lim EK, Lee H, Choi Y, et al. Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy. Biomaterials. 2016;105:12–24.

    Article  CAS  Google Scholar 

  31. Xing AY, Wang YW, Su ZX, Shi DB, Wang B, Gao P. Catenin-delta1, negatively regulated by miR-145, promotes tumour aggressiveness in gastric cancer. J Pathol. 2015;236:53–64.

    Article  CAS  Google Scholar 

  32. Shi DB, Ma RR, Zhang H, Hou F, Guo XY, Gao P. GAGE7B promotes tumor metastasis and growth via activating the p38delta/pMAPKAPK2/pHSP27 pathway in gastric cancer. J Exp Clin Cancer Res. 2019;38:124.

    Article  Google Scholar 

  33. Liu HT, Liu S, Liu L, Ma RR, Gao P. EGR1-mediated transcription of lncRNA-HNF1A-AS1 promotes cell-cycle progression in gastric cancer. Cancer Res. 2018;78:5877–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gupta PB, Kuperwasser C, Brunet JP, Ramaswamy S, Kuo WL, Gray JW, et al. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nat Genet. 2005;37:1047–54.

    Article  CAS  Google Scholar 

  35. Jung HY, Fattet L, Tsai JH, Kajimoto T, Chang Q, Newton AC, et al. Apical-basal polarity inhibits epithelial-mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation. Nat Cell Biol. 2019;21:359–71.

    Article  CAS  Google Scholar 

  36. Hansen BC, Gografe S, Pritt S, Jen KC, McWhirter CA, Barman SM, et al. Ensuring due process in the IACUC and animal welfare setting: considerations in developing noncompliance policies and procedures for institutional animal care and use committees and institutional officials. FASEB J. 2017;31:4216–25.

    Article  CAS  Google Scholar 

  37. Gao P, Zhou GY, Zhang QH, Su ZX, Zhang TG, Xiang L, et al. Lymphangiogenesis in gastric carcinoma correlates with prognosis. J Pathol. 2009;218:192–200.

    Article  Google Scholar 

  38. Tsai CY, Wang CS, Tsai MM, Chi HC, Cheng WL, Tseng YH, et al. Interleukin-32 increases human gastric cancer cell invasion associated with tumor progression and metastasis. Clin Cancer Res. 2014;20:2276–88.

    Article  CAS  Google Scholar 

  39. Sheng Y, Wang H, Liu D, Zhang C, Deng Y, Yang F, et al. Methylation of tumor suppressor gene CDH13 and SHP1 promoters and their epigenetic regulation by the UHRF1/PRMT5 complex in endometrial carcinoma. Gynecol Oncol. 2016;140:145–51.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant nos. 81672842 and 81872362), the Taishan Scholars Program of Shandong Province (Grant no. ts201511096).

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Correspondence to Peng Gao.

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Tian, Y., Ma, R., Sun, Y. et al. SP1-activated long noncoding RNA lncRNA GCMA functions as a competing endogenous RNA to promote tumor metastasis by sponging miR-124 and miR-34a in gastric cancer. Oncogene 39, 4854–4868 (2020). https://doi.org/10.1038/s41388-020-1330-4

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