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RETRACTED ARTICLE: microRNA-211-mediated targeting of the INHBA-TGF-β axis suppresses prostate tumor formation and growth

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This article was retracted on 20 May 2022

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Abstract

Prostate cancer (PCa) stem cells increase the sustainability of tumor growth, resulting in high relapse rates in patients with PCa. This goal of the present study was to elucidate the function of microRNA (miR)-211 in PCa stem cell activities. Based on the initial findings from the GSE26910 dataset, inhibin-β A (INHBA) was used for subsequent experiments, and miR-211 was then predicted as a candidate regulatory miR. Subsequently, INHBA and miR-211 were observed to be highly and poorly expressed in PCa tissues, respectively, and miR-211 negatively target INHBA. CD44+CD133+ cells were isolated, and both miR-211 and INHBA expression was altered in these cells to assess functional role of miR-211 and INHBA in PCa stem cells. Overexpression of miR-211 decreased expression of TGF-β1, TGF-β2, smad2, smad3, phosphorylated smad2 and smad3, and stem cell markers. miR-211 upregulation or INHBA knockdown resulted in reductions in the proliferation, invasion, colony-forming ability, sphere-forming ability, and stemness of PCa stem cells but enhanced their apoptosis in vitro. Furthermore, miR-211 upregulation or INHBA silencing decreased tumor growth and cell apoptosis in vivo. Taken together, these results indicate that upregulation of miR-211 has tumor-suppressive properties by inhibiting TGF-β pathway activation via INHBA in PCa stem cells.

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Fig. 1: Hsa-miR-211 might affect PCa progression by binding to 3′UTR of INHBA.
Fig. 2: Isolated CD44+CD133+ cells were selected for the subsequent analysis.
Fig. 3: MiR-211 inhibits activation of the TGF-β pathway by decreasing INHBA expression in PCa stem cells.
Fig. 4: Upregulation of miR-211 inhibits PCa stem cell proliferation and invasion while promoting apoptosis through inhibition of INHBA expression.
Fig. 5: Increased miR-211 expression inhibits the colony-forming ability, sphere-forming capacity, and stemness of PCa stem cells by suppressing INHBA.
Fig. 6: Upregulation of miR-211 impedes the growth rate of PCa tumors in nude mice.
Fig. 7: A mechanistic scheme demonstrating the regulatory role of miR-211 in the biological activities of PCa stem cells.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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References

  1. Pernar CH, Ebot EM, Wilson KM, Mucci LA. The Epidemiology of Prostate Cancer. Cold Spring Harb Perspect Med 2018;8:a030361.

  2. Dubey S, Vanveldhuizen P, Holzbeierlein J, Tawfik O, Thrasher JB, Karan D. Inflammation-associated regulation of the macrophage inhibitory cytokine (MIC-1) gene in prostate cancer. Oncol Lett 2012;3:1166–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kgatle MM, Kalla AA, Islam MM, Sathekge M, Moorad R. Prostate cancer: epigenetic alterations, risk factors, and therapy. Prostate Cancer 2016;2016:5653862.

    PubMed  PubMed Central  Google Scholar 

  4. Xu F, Gao Y, Wang Y, Pan J, Sha J, Shao X, et al. Decreased TSPAN1 promotes prostate cancer progression and is a marker for early biochemical recurrence after radical prostatectomy. Oncotarget 2016;7:63294–305.

    PubMed  PubMed Central  Google Scholar 

  5. Maitland NJ, Collins AT. Inflammation as the primary aetiological agent of human prostate cancer: a stem cell connection? J Cell Biochem 2008;105:931–9.

    CAS  PubMed  Google Scholar 

  6. Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, et al. Circular RNA: a new star of noncoding RNAs. Cancer Lett 2015;365:141–8.

    CAS  PubMed  Google Scholar 

  7. Fabris L, Ceder Y, Chinnaiyan AM, Jenster GW, Sorensen KD, Tomlins S, et al. The potential of microRNAs as prostate cancer biomarkers. Eur Urol 2016;70:312–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Al-Kafaji G, Al-Naieb ZT, Bakhiet M. Increased oncogenic microRNA-18a expression in the peripheral blood of patients with prostate cancer: a potential novel non-invasive biomarker. Oncol Lett 2016;11:1201–6.

    CAS  PubMed  Google Scholar 

  9. Mazar J, DeYoung K, Khaitan D, Meister E, Almodovar A, Goydos J, et al. The regulation of miRNA-211 expression and its role in melanoma cell invasiveness. PLoS ONE 2010;5:e13779.

    PubMed  PubMed Central  Google Scholar 

  10. Tao F, Tian X, Ruan S, Shen M, Zhang Z. miR-211 sponges lncRNA MALAT1 to suppress tumor growth and progression through inhibiting PHF19 in ovarian carcinoma. FASEB J. 2018. https://doi.org/10.1096/fj.201800495RRfj201800495RR.

  11. Xu Y, Brenn T, Brown ER, Doherty V, Melton DW. Differential expression of microRNAs during melanoma progression: miR-200c, miR-205 and miR-211 are downregulated in melanoma and act as tumour suppressors. Br J Cancer 2012;106:553–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang T, Hao D, Yang S, Ma J, Yang W, Zhu Y, et al. miR-211 facilitates platinum chemosensitivity by blocking the DNA damage response (DDR) in ovarian cancer. Cell Death Dis 2019;10:495.

    PubMed  PubMed Central  Google Scholar 

  13. Hao P, Kang B, Yao G, Hao W, Ma F. MicroRNA-211 suppresses prostate cancer proliferation by targeting SPARC. Oncol Lett 2018;15:4323–9.

    PubMed  PubMed Central  Google Scholar 

  14. Jiang L, Si T, Yu M, Zeng X, Morse HC III, Lu Y, et al. The tumor suppressive role of inhibin betaA in diffuse large B-cell lymphoma. Leuk Lymphoma 2018;59:1202–12.

    CAS  PubMed  Google Scholar 

  15. Okano M, Yamamoto H, Ohkuma H, Kano Y, Kim H, Nishikawa S, et al. Significance of INHBA expression in human colorectal cancer. Oncol Rep. 2013;30:2903–8.

    CAS  PubMed  Google Scholar 

  16. Zheng Y, Gao Y, Li X, Si S, Xu H, Qi F, et al. Long non-coding RNA NAP1L6 promotes tumor progression and predicts poor prognosis in prostate cancer by targeting Inhibin-beta A. OncoTargets Ther 2018;11:4965–77.

    Google Scholar 

  17. Chen ZL, Qin L, Peng XB, Hu Y, Liu B. INHBA gene silencing inhibits gastric cancer cell migration and invasion by impeding activation of the TGF-beta signaling pathway. J Cell Physiol 2019;234:18065–74.

    CAS  PubMed  Google Scholar 

  18. Walker L, Millena AC, Strong N, Khan SA. Expression of TGFbeta3 and its effects on migratory and invasive behavior of prostate cancer cells: involvement of PI3-kinase/AKT signaling pathway. Clin Exp Metastasis 2013;30:13–23.

    CAS  PubMed  Google Scholar 

  19. Planche A, Bacac M, Provero P, Fusco C, Delorenzi M, Stehle JC, et al. Identification of prognostic molecular features in the reactive stroma of human breast and prostate cancer. PLoS ONE 2011;6:e18640.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Xu J, Lu MX, Cui YD, Du YZ. Selection and evaluation of reference genes for expression analysis using qRT-PCR in chilo suppressalis (lepidoptera: pyralidae). J Econ Entomol 2017;110:683–91.

    CAS  PubMed  Google Scholar 

  21. Kim SJ, Kim DH, Kang D, Kim JH. Expression of anterior gradient 2 is decreased with the progression of human biliary tract cancer. Tohoku J Exp Med 2014;234:83–8.

    PubMed  Google Scholar 

  22. Chanda D, Lee JH, Sawant A, Hensel JA, Isayeva T, Reilly SD, et al. Anterior gradient protein-2 is a regulator of cellular adhesion in prostate cancer. PLoS ONE 2014;9:e89940.

    PubMed  PubMed Central  Google Scholar 

  23. Ho ME, Quek SI, True LD, Morrissey C, Corey E, Vessella RL, et al. Prostate cancer cell phenotypes based on AGR2 and CD10 expression. Mod Pathol 2013;26:849–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. da Silva EG. Suturoscope: a new device that allows endoscopic sutures to be performed with traditional threads. Surg Endosc 1990;4:220–3.

    PubMed  Google Scholar 

  25. Shu Y, Ren L, Xie B, Liang Z, Chen J. MiR-204 enhances mitochondrial apoptosis in doxorubicin-treated prostate cancer cells by targeting SIRT1/p53 pathway. Oncotarget 2017;8:97313–22.

    PubMed  PubMed Central  Google Scholar 

  26. Chen Q, Li Y, Zhou X, Li R. Oxibendazole inhibits prostate cancer cell growth. Oncol Lett 2018;15:2218–26.

    PubMed  Google Scholar 

  27. Wu G, Wang J, Chen G, Zhao X. microRNA-204 modulates chemosensitivity and apoptosis of prostate cancer cells by targeting zinc-finger E-box-binding homeobox 1 (ZEB1). Am J Transl Res 2017;9:3599–610.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shephard RJ. Physical activity and prostate cancer: an updated review. Sports Med 2017;47:1055–73.

    PubMed  Google Scholar 

  29. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 2011;17:211–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Xia B, Yang S, Liu T, Lou G. miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6. Mol Cancer 2015;14:57.

    PubMed  PubMed Central  Google Scholar 

  31. Sakurai E, Maesawa C, Shibazaki M, Yasuhira S, Oikawa H, Sato M, et al. Downregulation of microRNA-211 is involved in expression of preferentially expressed antigen of melanoma in melanoma cells. Int J Oncol 2011;39:665–72.

    CAS  PubMed  Google Scholar 

  32. Mor E, Shomron N. Species-specific microRNA regulation influences phenotypic variability: perspectives on species-specific microRNA regulation. Bioessays 2013;35:881–8.

    CAS  PubMed  Google Scholar 

  33. Li X, Yang Z, Xu S, Wang Z, Jin P, Yang X, et al. Targeting INHBA in ovarian cancer cells suppresses cancer xenograft growth by attenuating stromal fibroblast activation. Dis Markers 2019;2019:7275289.

    PubMed  PubMed Central  Google Scholar 

  34. Lyu S, Jiang C, Xu R, Huang Y, Yan S. INHBA upregulation correlates with poorer prognosis in patients with esophageal squamous cell carcinoma. Cancer Manag Res 2018;10:1585–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee HY, Li CC, Huang CN, Li WM, Yeh HC, Ke HL, et al. INHBA overexpression indicates poor prognosis in urothelial carcinoma of urinary bladder and upper tract. J Surg Oncol 2015;111:414–22.

    CAS  PubMed  Google Scholar 

  36. Gasi Tandefelt D, Boormans JL, van der Korput HA, Jenster GW, Trapman J. A 36-gene signature predicts clinical progression in a subgroup of ERG-positive prostate cancers. Eur Urol 2013;64:941–50.

    CAS  PubMed  Google Scholar 

  37. Karagiannidis C, Hense G, Martin C, Epstein M, Ruckert B, Mantel PY, et al. Activin A is an acute allergen-responsive cytokine and provides a link to TGF-beta-mediated airway remodeling in asthma. J Allergy Clin Immunol 2006;117:111–8.

    CAS  PubMed  Google Scholar 

  38. Dai X, Rao C, Li H, Chen Y, Fan L, Geng H, et al. Regulation of pigmentation by microRNAs: MITF-dependent microRNA-211 targets TGF-beta receptor 2. Pigment Cell Melanoma Res 2015;28:217–22.

    CAS  PubMed  Google Scholar 

  39. Kimbrough-Allah MN, Millena AC, Khan SA. Differential role of PTEN in transforming growth factor beta (TGF-beta) effects on proliferation and migration in prostate cancer cells. Prostate 2018;78:377–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Song B, Park SH, Zhao JC, Fong KW, Li S, Lee Y, et al. Targeting FOXA1-mediated repression of TGF-beta signaling suppresses castration-resistant prostate cancer progression. J Clin Invest 2019;129:569–82.

    PubMed  Google Scholar 

  41. Wamsley JJ, Kumar M, Allison DF, Clift SH, Holzknecht CM, Szymura SJ, et al. Activin upregulation by NF-kappaB is required to maintain mesenchymal features of cancer stem-like cells in non-small cell lung cancer. Cancer Res 2015;75:426–35.

    CAS  PubMed  Google Scholar 

  42. Togashi Y, Kogita A, Sakamoto H, Hayashi H, Terashima M, de Velasco MA, et al. Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer. Cancer Lett 2015;356:819–27.

    CAS  PubMed  Google Scholar 

  43. Seder CW, Hartojo W, Lin L, Silvers AL, Wang Z, Thomas DG, et al. INHBA overexpression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcinoma. J Thorac Oncol 2009;4:455–62.

    PubMed  Google Scholar 

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Acknowledgements

We would like to acknowledge the reviewers for their helpful comments on this paper.

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ZZ and KW conceived and designed the research, ST and KW participated in the data collection and the data interpretation, ZZ and KW drafted and completed manuscript. All authors read and approved the final manuscript.

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Correspondence to Kai Wang or Shanfeng Tan.

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This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1038/s41417-022-00481-2

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Zhao, Z., Wang, K. & Tan, S. RETRACTED ARTICLE: microRNA-211-mediated targeting of the INHBA-TGF-β axis suppresses prostate tumor formation and growth. Cancer Gene Ther 28, 514–528 (2021). https://doi.org/10.1038/s41417-020-00237-w

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