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Downregulation of SBF2-AS1 functions as a tumor suppressor in clear cell renal cell carcinoma by inhibiting miR-338-3p-targeted ETS1

Cancer Gene Therapy volume 28, pages 813–827 (2021)Cite this article

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Abstract

Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of kidney cancer in adults, accompanied by an increasing incidence rate worldwide. We found that SBF2-AS1 was a differentially expressed long-noncoding RNA (lncRNA) in ccRCC through the microarray-based expression analyses. The aim of the present study was to explore the role of SBF2-AS1 in ccRCC development by assessing its effects on cellular processes and further investigate the underlying mechanism. SBF2-AS1 was found to be highly expressed in ccRCC tissues and cells. Ectopic expression and knockdown of SBF2-AS1 and miR-338-3p were performed in ccRCC 768-O cells to explore their effects on cell proliferation, migration, invasion, apoptosis and autophagy by EdU assay, scratch test, Transwell assay, calcein-AM/PI, and GFP-LC3 immunofluorescence assays, respectively. The interactions among SBF2-AS1, miR-338-3p and ETS1 were analyzed using dual-luciferase reporter, RIP and RNA pull-down assays. SBF2-AS1 specifically bound to miR-338-3p and inhibited its expression. Moreover, ETS1 was targeted by miR-338-3p. The knockdown of SBF2-AS1 or ETS1 or overexpression of miR-338-3p resulted in reduced cell proliferation, migration and invasion but elevated cell apoptosis and autophagy. In vivo experiments verified the tumor-suppressive role of silencing SBF2-AS1 in tumor growth of nude mice xenografted with ccRCC cells. Thus, silencing SBF2-AS1 exerted suppressive effects on ccRCC by elevating miR-338-3p and suppressing ETS1.

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Fig. 1: SBF2-AS1 overexpression results in increased ccRCC cell proliferation, migration and invasion.
Fig. 2: SBF2-AS1 binds to miR-338-3 to inhibit miR-338-3p expression.
Fig. 3: miR-338-3p mediates biological functions of ccRCC cells by inhibiting ETS1.
Fig. 4: SBF2-AS1 regulates biological functions of ccRCC cells through downregulating miR-338-3p and upregulating ETS1.
Fig. 5: SBF2-AS1 promotes tumor growth in nude mice via miR-338-3p and ETS1.
Fig. 6: The mechanism of SBF2-AS1 in ccRCC.

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The datasets generated/analysed during the current study are available.

References

  1. Montironi R, Mazzucchelli R, Scarpelli M, Lopez-Beltran A, Cheng L. Update on selected renal cell tumors with clear cell features. With emphasis on multilocular cystic clear cell renal cell carcinoma. Histol Histopathol. 2013;28:1555–66.

    CAS  PubMed  Google Scholar 

  2. Lane BR, Li J, Zhou M, Babineau D, Faber P, Novick AC, et al. Differential expression in clear cell renal cell carcinoma identified by gene expression profiling. J Urol. 2009;181:849–60.

    Article  Google Scholar 

  3. Wang Y, Gao W, Xu J, Zhu Y, Liu L. The long noncoding RNA urothelial carcinoma-associated 1 overexpression as a poor prognostic biomarker in clear cell renal cell carcinoma. Tumour Biol. 2017;39:1010428317698377.

    PubMed  Google Scholar 

  4. Kabel AM, Atef A, Estfanous RS. Ameliorative potential of sitagliptin and/or resveratrol on experimentally-induced clear cell renal cell carcinoma. Biomed Pharmacother. 2018;97:667–74.

    Article  CAS  Google Scholar 

  5. Shi X, Sun M, Liu H, Yao Y, Song Y. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett. 2013;339:159–66.

    Article  CAS  Google Scholar 

  6. Zhao QS, Li L, Zhang L, Meng XW, Li LL, Ge XF, et al. Over-expression of lncRNA SBF2-AS1 is associated with advanced tumor progression and poor prognosis in patients with non-small cell lung cancer. Eur Rev Med Pharm Sci. 2016;20:3031–4.

    Google Scholar 

  7. Lv J, Qiu M, Xia W, Liu C, Xu Y, Wang J, et al. High expression of long non-coding RNA SBF2-AS1 promotes proliferation in non-small cell lung cancer. J Exp Clin Cancer Res. 2016;35:75.

    Article  Google Scholar 

  8. Gao F, Feng J, Yao H, Li Y, Xi J, Yang J. LncRNA SBF2-AS1 promotes the progression of cervical cancer by regulating miR-361-5p/FOXM1 axis. Artif Cells Nanomed Biotechnol. 2019;47:776–82.

    Article  CAS  Google Scholar 

  9. Chen G, Gu Y, Han P, Li Z, Zhao JL, Gao MZ. Long noncoding rna sbf2-as1 promotes colorectal cancer proliferation and invasion by inhibiting mir-619-5p activity and facilitating hdac3 expression. J Cell Physiol. 2019;234:18688–96.

    Article  CAS  Google Scholar 

  10. Chen R, Xia W, Wang X, Qiu M, Yin R, Wang S, et al. Upregulated long non-coding RNA SBF2-AS1 promotes proliferation in esophageal squamous cell carcinoma. Oncol Lett. 2018;15:5071–80.

    PubMed  PubMed Central  Google Scholar 

  11. Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505:344–52.

    Article  CAS  Google Scholar 

  12. Barbato S, Solaini G, Fabbri M. MicroRNAs in oncogenesis and tumor suppression. Int Rev Cell Mol Biol. 2017;333:229–68.

    Article  CAS  Google Scholar 

  13. Jin Y, Zhao M, Xie Q, Zhang H, Wang Q, Ma Q. MicroRNA-338-3p functions as tumor suppressor in breast cancer by targeting SOX4. Int J Oncol. 2015;47:1594–602.

    Article  CAS  Google Scholar 

  14. Huang Y, Wu Y, Zeng L, Shan W, Huang L. The tumor suppressor role of microRNA-338-3p in renal cell carcinoma. Oncol Lett. 2018;16:2195–200.

    PubMed  PubMed Central  Google Scholar 

  15. Zhao W, Zhang S, Wang X, Ma X, Huang B, Chen H, et al. ETS1 targets RYBP transcription to inhibit tumor cell proliferation. Biochem Biophys Res Commun. 2019;509:810–16.

    Article  CAS  Google Scholar 

  16. Ma N, Chen F, Shen SL, Chen W, Chen LZ, Su Q, et al. MicroRNA-129-5p inhibits hepatocellular carcinoma cell metastasis and invasion via targeting ETS1. Biochem Biophys Res Commun. 2015;461:618–23.

    Article  CAS  Google Scholar 

  17. Zhang Y, Yan LX, Wu QN, Du ZM, Chen J, Liao DZ, et al. miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. Cancer Res. 2011;71:3552–62.

    Article  CAS  Google Scholar 

  18. Gautier L, Cope L, Bolstad BM, Irizarry RA. affy–analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–15.

    Article  CAS  Google Scholar 

  19. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:3.

    Article  Google Scholar 

  20. Xie Y, Ma X, Li H, Gao Y, Gu L, Chen L, et al. Prognostic value of clinical and pathological features in chinese patients with chromophobe renal cell carcinoma: a 10-year single-center study. J Cancer. 2017;8:3474–79.

    Article  Google Scholar 

  21. Santiago JM, Sasako M, Osorio J. TNM-7th edition 2009 (UICC/AJCC) and Japanese Classification 2010 in Gastric Cancer. Towards simplicity and standardisation in the management of gastric cancer. Cir Esp. 2011;89:275–81.

  22. Li G, Xie ZK, Zhu DS, Guo T, Cai QL, Wang Y. KIF20B promotes the progression of clear cell renal cell carcinoma by stimulating cell proliferation. J Cell Physiol. 2019. https://doi.org/10.1002/jcp.28322.

  23. Zeng MH, Qiu JG, Xu Y, Zhang XH. IDUA, NDST1, SAP30L, CRYBA4, and SI as novel prognostic signatures clear cell renal cell carcinoma. J Cell Physiol. 2019. https://doi.org/10.1002/jcp.28297.

  24. Tian YJ, Wang YH, Xiao AJ, Li PL, Guo J, Wang TJ, et al. Long noncoding RNA SBF2-AS1 act as a ceRNA to modulate cell proliferation via binding with miR-188-5p in acute myeloid leukemia. Artif Cells Nanomed Biotechnol. 2019;47:1730–37.

    Article  CAS  Google Scholar 

  25. Yu H, Zheng J, Liu X, Xue Y, Shen S, Zhao L, et al. Transcription factor NFAT5 promotes glioblastoma cell-driven angiogenesis via SBF2-AS1/miR-338-3p-mediated EGFL7 expression change. Front Mol Neurosci. 2017;10:301.

    Article  Google Scholar 

  26. Chen R, Xia W, Wang S, Xu Y, Ma Z, Xu W, et al. Long noncoding RNA SBF2-AS1 is critical for tumorigenesis of early-stage lung adenocarcinoma. Mol Ther Nucleic Acids. 2019;16:543–53.

    Article  CAS  Google Scholar 

  27. Guo B, Liu L, Yao J, Ma R, Chang D, Li Z, et al. miR-338-3p suppresses gastric cancer progression through a PTEN-AKT axis by targeting P-REX2a. Mol Cancer Res. 2014;12:313–21.

    Article  CAS  Google Scholar 

  28. Yu L, Shang ZF, Hsu FM, Zhang Z, Tumati V, Lin YF, et al. NSCLC cells demonstrate differential mode of cell death in response to the combined treatment of radiation and a DNA-PKcs inhibitor. Oncotarget. 2015;6:3848–60.

    Article  Google Scholar 

  29. Cao B, Tan S, Tang H, Chen Y, Shu P. miR5125p suppresses proliferation, migration and invasion, and induces apoptosis in nonsmall cell lung cancer cells by targeting ETS1. Mol Med Rep. 2019;19:3604–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Puzovic V, Brcic I, Ranogajec I, Jakic-Razumovic J. Prognostic values of ETS-1, MMP-2 and MMP-9 expression and co-expression in breast cancer patients. Neoplasma. 2014;61:439–46.

    Article  CAS  Google Scholar 

  31. Yamaguchi E, Nakayama T, Nanashima A, Matsumoto K, Yasutake T, Sekine I, et al. Ets-1 proto-oncogene as a potential predictor for poor prognosis of lung adenocarcinoma. Tohoku J Exp Med. 2007;213:41–50.

    Article  CAS  Google Scholar 

  32. Wang H, Chen W, Yang P, Zhou J, Wang K, Tao Q. Knockdown of linc00152 inhibits the progression of gastric cancer by regulating microRNA-193b-3p/ETS1 axis. Cancer Biol Ther. 2019;20:461–73.

    Article  CAS  Google Scholar 

  33. Zhang L, Yan R, Zhang SN, Zhang HZ, Ruan XJ, Cao Z, et al. MicroRNA-338-3p inhibits the progression of bladder cancer through regulating ETS1 expression. Eur Rev Med Pharm Sci. 2019;23:1986–95.

    CAS  Google Scholar 

  34. Sun Q, Jiang CW, Tan ZH, Hou LY, Dong H, Liu K, et al. MiR-222 promotes proliferation, migration and invasion of lung adenocarcinoma cells by targeting ETS1. Eur Rev Med Pharm Sci. 2017;21:2385–91.

    CAS  Google Scholar 

  35. Zhang X, Wang C, Li H, Niu X, Liu X, Pei D, et al. miR-338-3p inhibits the invasion of renal cell carcinoma by downregulation of ALK5. Oncotarget. 2017;8:64106–13.

    Article  Google Scholar 

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Acknowledgements

We acknowledge and appreciate our colleagues for their valuable suggestions and technical assistance for this study.

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Authors and Affiliations

  1. Department of Nephrology, Linyi People’s Hospital, Linyi, 276000, P.R. China

    Xiuqin Yang

  2. Department of Endocrinology, Linyi People’s Hospital, Linyi, 276000, P.R. China

    Yuanyuan Zhang

  3. Hemodialysis Room, Linyi People’s Hospital, Linyi, 276000, P.R. China

    Haiying Fan

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Contributions

XY, YZ, and HF designed the study. XY collated the data, carried out data analyses and produced the initial draft of the manuscript. YZ and HF contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Haiying Fan.

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The authors declare that they have no conflict of interest.

Ethical approval

This study was performed with the approval of the ethics committee of Linyi People’s Hospital and guided by the Declaration of Helsinki. All participants signed the informed consent documentations. Animal experiments were approved by the Institutional Animal Care and Use Committee of Linyi People’s Hospital. Efforts were made to avoid all unnecessary distress to the animals.

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Yang, X., Zhang, Y. & Fan, H. Downregulation of SBF2-AS1 functions as a tumor suppressor in clear cell renal cell carcinoma by inhibiting miR-338-3p-targeted ETS1. Cancer Gene Ther 28, 813–827 (2021). https://doi.org/10.1038/s41417-020-0197-4

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