Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

RETRACTED ARTICLE: miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A

Gene Therapy volume 29, pages 28–40 (2022)Cite this article

Subjects

This article was retracted on 06 September 2024

This article has been updated

Abstract

MicroRNAs (miRNAs) are considered important in the pathogenesis of colon cancer. But the mechanism of their role in colon cancer is still largely unknown. Here, we aimed to explore the function of miR-503-5p in the pathogenesis of colon cancer. This study analyzed miRNA microarray of colon cancer. Then, we performed EdU, CCK-8, flow cytometry, Transwell invasion assays and in vivo assays to explore the exact role of miR-503-5p in colon cancer. We observed considerable downregulation of miR-503-5p expression in colon cancer cells and tissues and significant correlation with the TNM stage, differentiation grade and lymph node metastasis of colon cancer. Overexpression of miR-503-5p promoted the apoptosis and G1 arrest of colon cancer cells, and inhibited migration, proliferation, invasion and colony formation. Interestingly, ectopic miR-503-5p overexpression could significantly inhibit vascular endothelial growth factor (VEGF)-A expression and reduce the activity of a luciferase reporter containing the VEGF-A 3′-untranslated region. Furthermore, overexpressed miR-503-5p in human umbilical vein endothelial cells (HUVECs) and colon cancer cells resulted in lower expression levels of VEGFR-2, and subsequently inhibited AKT signaling pathway. Additionally, overexpression of miR-503-5p suppressed both lymphangiogenesis and angiogenesis in vivo and significantly inhibited the tumorigenicity of HT-29 cells in nude mice. In summary, our study shows downregulation of miR-503-5p at least partially contributes to the tumorigenesis of colon cancer through modulating the angiogenesis and lymphangiogenesis by targeting VEGF-A while stimulating AKT signaling pathways. Therapeutic strategies to restore miR-503-5p in colon cancer could be useful to inhibit tumor progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: miR-503-5p expression in colon cancer tissues and its clinical value.
Fig. 2: Effects of miR-503-5p overexpression on proliferation and apoptosis of colon cancer cells in vitro.
Fig. 3: Ectopic miR-503-5p expression inhibited migration and invasion of colon cancer cells.
Fig. 4: miR-503-5p directly targeted VEGF-A.
Fig. 5: miR-503-5p inhibited tumor growth, lymphangiogenesis and angiogenesis in vivo.
Fig. 6: Overexpression of miR-503-5p inhibited tube formation of HUVECs.
Fig. 7: Hypothetical model of miR-503-5p suppressive roles in colon cancer cells and endothelial cells.

Similar content being viewed by others

Data availability

Upon reasonable request, the datasets used and analyzed during the present study are available from the corresponding author.

Change history

References

  1. Zeng M, Zhu L, Li L, Kang C. miR-378 suppresses the proliferation, migration and invasion of colon cancer cells by inhibiting SDAD1. Cell Mol Biol Lett. 2017;22:12.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352:476–87.

    Article  CAS  PubMed  Google Scholar 

  3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  PubMed  Google Scholar 

  4. Zhao J, Chen Y, Liu F, Yin M. Overexpression of miRNA-143 inhibits colon cancer cell proliferation by inhibiting glucose uptake. Arch Med Res. 2018;49:497–503.

    Article  CAS  PubMed  Google Scholar 

  5. Uppada SB, Gowrikumar S, Ahmad R, Kumar B, Szeglin B, Chen X, et al. MASTL induces colon cancer progression and chemoresistance by promoting Wnt/beta-catenin signaling. Mol Cancer. 2018;17:111.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Steck SE, Butler LM, Keku T, Antwi S, Galanko J, Sandler RS, et al. Nucleotide excision repair gene polymorphisms, meat intake and colon cancer risk. Mutat Res. 2014;762:24–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Canote R, Du Y, Carling T, Tian F, Peng Z, Huang S. The tumor suppressor gene RIZ in cancer gene therapy (review). Oncol Rep. 2002;9:57–60.

    CAS  PubMed  Google Scholar 

  8. Wang LH, Wu CF, Rajasekaran N, Shin YK. Loss of tumor suppressor gene function in human cancer: an overview. Cell Physiol Biochem. 2018;51:2647–93.

    Article  CAS  PubMed  Google Scholar 

  9. Bultman SJ. Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer. Mol Nutr Food Res. 2017;61:1500902.

    Article  Google Scholar 

  10. Menzel P, McCorkindale AL, Stefanov SR, Zinzen RP, Meyer IM. Transcriptional dynamics of microRNAs and their targets during Drosophila neurogenesis. RNA Biol. 2019;16:69–81.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Tarallo A, Carissimo A, Gatto F, Nusco E, Toscano A, Musumeci O, et al. microRNAs as biomarkers in Pompe disease. Genet Med. 2019;21:591–600.

    Article  CAS  PubMed  Google Scholar 

  12. Chen X, Xie D, Zhao Q, You ZH. MicroRNAs and complex diseases: from experimental results to computational models. Brief Bioinform. 2019;20:515–39.

    Article  CAS  PubMed  Google Scholar 

  13. Hibner G, Kimsa-Furdzik M, Francuz T. Relevance of microRNAs as potential diagnostic and prognostic markers in colorectal cancer. Int J Mol Sci. 2018;19:2944.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Qadir MI, Faheem A. miRNA: a diagnostic and therapeutic tool for pancreatic cancer. Crit Rev Eukaryot Gene Expr. 2017;27:197–204.

    Article  PubMed  Google Scholar 

  15. Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12.

    Article  CAS  PubMed  Google Scholar 

  16. Xu Q, Tong JL, Zhang CP, Xiao Q, Lin XL, Xiao XY. miR-27a induced by colon cancer cells in HLECs promotes lymphangiogenesis by targeting SMAD4. PLoS ONE. 2017;12:e0186718.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tsuchida A, Ohno S, Wu W, Borjigin N, Fujita K, Aoki T, et al. miR-92 is a key oncogenic component of the miR-17-92 cluster in colon cancer. Cancer Sci. 2011;102:2264–71.

    Article  CAS  PubMed  Google Scholar 

  18. Valeri N, Braconi C, Gasparini P, Murgia C, Lampis A, Paulus-Hock V, et al. MicroRNA-135b promotes cancer progression by acting as a downstream effector of oncogenic pathways in colon cancer. Cancer Cell. 2014;25:469–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang Y, Lin C, Liao G, Liu S, Ding J, Tang F, et al. MicroRNA-506 suppresses tumor proliferation and metastasis in colon cancer by directly targeting the oncogene EZH2. Oncotarget. 2015;6:32586–601.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Cheng J, Deng R, Zhang P, Wu C, Wu K, Shi L, et al. miR-219-5p plays a tumor suppressive role in colon cancer by targeting oncogene Sall4. Oncol Rep. 2015;34:1923–32.

    Article  CAS  PubMed  Google Scholar 

  21. Bao L, Chau C, Bao J, Tsoukas MM, Chan LS. IL-4 dysregulates microRNAs involved in inflammation, angiogenesis and apoptosis in epidermal keratinocytes. Microbiol Immunol. 2018;62:732–6.

    Article  CAS  PubMed  Google Scholar 

  22. Hunter S, Nault B, Ugwuagbo KC, Maiti S, Majumder M. Mir526b and Mir655 promote tumour associated angiogenesis and lymphangiogenesis in breast cancer. Cancers. 2019;11:938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li X, Han X, Yang J, Sun J, Wei P. miR-503-5p inhibits the proliferation of T24 and EJ bladder cancer cells by interfering with the Rb/E2F signaling pathway. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017;33:1360–4.

    PubMed  Google Scholar 

  24. Sun Y, Li L, Xing S, Pan Y, Shi Y, Zhang L, et al. miR-503-3p induces apoptosis of lung cancer cells by regulating p21 and CDK4 expression. Cancer Biomark. 2017;20:597–608.

    Article  CAS  PubMed  Google Scholar 

  25. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21:154–65.

    Article  CAS  PubMed  Google Scholar 

  26. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    Article  CAS  PubMed  Google Scholar 

  27. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Investig. 2004;113:1040–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Halin C, Tobler NE, Vigl B, Brown LF, Detmar M. VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood. 2007;110:3158–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med. 2002;196:1497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Matsumoto K, Ema M. Roles of VEGF-A signalling in development, regeneration, and tumours. J Biochem. 2014;156:1–10.

    Article  CAS  PubMed  Google Scholar 

  31. Roskoski R Jr. Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas. Pharmacol Res. 2017;120:116–32.

    Article  CAS  PubMed  Google Scholar 

  32. Malinda KM. In vivo matrigel migration and angiogenesis assay. Methods Mol Biol. 2009;467:287–94.

    Article  CAS  PubMed  Google Scholar 

  33. Feng Y, Hu J, Ma J, Feng K, Zhang X, Yang S, et al. RNAi-mediated silencing of VEGF-C inhibits non-small cell lung cancer progression by simultaneously down-regulating the CXCR4, CCR7, VEGFR-2 and VEGFR-3-dependent axes-induced ERK, p38 and AKT signalling pathways. Eur J Cancer. 2011;47:2353–63.

    Article  CAS  PubMed  Google Scholar 

  34. Minna E, Romeo P, Dugo M, De Cecco L, Todoerti K, Pilotti S, et al. miR-451a is underexpressed and targets AKT/mTOR pathway in papillary thyroid carcinoma. Oncotarget. 2016;7:12731–47.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Aghaee-Bakhtiari SH, Arefian E, Naderi M, Noorbakhsh F, Nodouzi V, Asgari M, et al. MAPK and JAK/STAT pathways targeted by miR-23a and miR-23b in prostate cancer: computational and in vitro approaches. Tumour Biol. 2015;36:4203–12.

    Article  CAS  PubMed  Google Scholar 

  36. Park GB, Kim D. MicroRNA-503-5p inhibits the CD97-mediated JAK2/STAT3 pathway in metastatic or paclitaxel-resistant ovarian cancer cells. Neoplasia. 2019;21:206–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jiao LR, Frampton AE, Jacob J, Pellegrino L, Krell J, Giamas G, et al. MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors. PLoS ONE. 2012;7:e32068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Murugan AK, Munirajan AK, Alzahrani AS. MicroRNAs: modulators of the Ras oncogenes in oral cancer. J Cell Physiol. 2016;231:1424–31.

    Article  CAS  PubMed  Google Scholar 

  39. Barisciano G, Colangelo T, Rosato V, Muccillo L, Letizia Taddei M, Ippolito L, et al. miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer. Br J Cancer. 2020;122:1354–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yamamoto H, Mori M. MicroRNAs as therapeutic targets and colorectal cancer therapeutics. Adv Exp Med Biol. 2016;937:239–47.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I extend my sincere gratitude to my administrator Na Zhang, for her instructive advice and useful suggestion on my thesis. Specially thanks to Shenglong Li, for his valuable suggestions, guidance, and help in the completion of this article. Without his consistent and illuminating instructions, this thesis could not have reached its present form.

Author information

Authors and Affiliations

  1. Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, China

    Linlin Wei, Chaonan Sun, Yaotian Zhang, Ning Han & Shichen Sun

Authors
  1. Linlin Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chaonan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yaotian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ning Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shichen Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LW designed the study. CS and SS performed the experiments. YZ analyzed the data. NH drafted this manuscript. LW reviewed and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Linlin Wei.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article has been retracted. Please see the retraction notice for more detail: https://doi.org/10.1038/s41434-024-00486-6"

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wei, L., Sun, C., Zhang, Y. et al. RETRACTED ARTICLE: miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A. Gene Ther 29, 28–40 (2022). https://doi.org/10.1038/s41434-020-0167-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41434-020-0167-3

This article is cited by

Search

Advanced search

Quick links