Skip to main content

Advertisement

SpringerLink
Log in

Antisense-miR-21 enhances differentiation/apoptosis and reduces cancer stemness state on anaplastic thyroid cancer

  • Original Article
  • Published:
Tumor Biology

Abstract

Anaplastic thyroid carcinoma (ATC) is the most aggressive malignancy in thyroid cancers. Resistance to current therapies is still a challenge. MicroRNAs are a class of small non-coding RNAs, regulating gene expression. MiR-21 is an oncomiR that is overexpressed in nearly all cancers including ATC. Accumulating evidence suggested that miR-21 has a role in cancer stemness state, apoptosis, cell cycle progression, and differentiation. Therefore, we evaluated the application of Off-miR-21 to sequester the microRNA for therapeutic purposes on ATC cell lines. In this study, C643 and SW1736 were transducted by hsa-miR-21 antagomir (Off-miR-21). PTEN gene expression was performed as a known target of miR-21. Stemness state in cancer stem cells (CSCs) was evaluated by the changes of CSC biomarkers including Oct-4 and ABCG2. Apoptosis was assessed by PDCD4 and Mcl-1 gene expression and flow cytometry. Sodium/iodide symporter (NIS) and thyroglobulin (TG) were measured as ATC differentiation markers. In addition, cell cycle progression was investigated via the alterations of p21 gene expression and flow cytometry. Specific downregulation of miR-21 induced the differentiation and apoptosis in C643 and SW1736. Inversely, the treatment inhibited stemness state and cell cycle progression. Knockdown of miR-21 significantly increased the expression of PDCD4, p21, NIS, and TG while leading to decreased expression of Oct-4, ABCG2, and Mcl-1.Taken together, the results suggest that miR-21, as an oncomiR, has a role not only in stemness state but also in tumor growth, differentiation, and apoptosis. Hence, suppression of miR-21 could pave the way for ATC therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sipos J, Mazzaferri E. Thyroid cancer epidemiology and prognostic variables. Clin Oncol. 2010;22:395–404.

    Article  CAS  Google Scholar 

  2. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA. 2006;295:2164–7.

    Article  CAS  PubMed  Google Scholar 

  3. Pierie J-PE, Muzikansky A, Gaz RD, Faquin WC, Ott MJ. The effect of surgery and radiotherapy on outcome of anaplastic thyroid carcinoma. Ann Surg Oncol. 2002;9:57–64.

    Article  PubMed  Google Scholar 

  4. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.

    Article  CAS  PubMed  Google Scholar 

  5. Guo Z, Hardin H, Lloyd RV. Cancer stem-like cells and thyroid cancer. Endocr Relat Cancer. 2014;21:T285–300.

    Article  CAS  PubMed  Google Scholar 

  6. Ma R, Minsky N, Morshed SA, Davies TF. Stemness in human thyroid cancers and derived cell lines: the role of asymmetrically dividing cancer stem cells resistant to chemotherapy. J Clin Endocrinol Metab. 2014;99:E400–E9.

  7. Lin RY. Thyroid cancer stem cells. Nat Rev Endocrinol. 2011;7:609–16.

    Article  CAS  PubMed  Google Scholar 

  8. Gao Y-J, Li B, Wu X-Y, Cui J, Han J-K. Thyroid tumor-initiating cells: increasing evidence and opportunities for anticancer therapy (review). Oncol Rep. 2014;31:1035–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Xing M. Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer. Thyroid. 2010;20:697–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hill R, Wu H. PTEN, stem cells, and cancer stem cells. J Biol Chem. 2009;284:11755–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Riesco-Eizaguirre G, Santisteban P. A perspective view of sodium iodide symporter research and its clinical implications. Eur J Endocrinol. 2006;155:495–512.

    Article  CAS  PubMed  Google Scholar 

  12. Paes JE, Ringel MD. Dysregulation of the phosphatidylinositol 3-kinase pathway in thyroid neoplasia. Endocrinol Metab Clin North Am. 2008;37:375–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13:283–96.

    CAS  PubMed  Google Scholar 

  14. Samimi H, Zaki dizaji M, Ghadami M, Shahzadeh fazeli A, Khashayar P, Soleimani M, et al. MicroRNAs networks in thyroid cancers: focus on miRNAs related to the fascin. J Diabetes MetabDisord. 2013;12:31.

    Google Scholar 

  15. Selcuklu SD, Donoghue MA. Spillane C: miR-21 as a key regulator of oncogenic processes. Biochem Soc Trans. 2009;37:918–25.

    Article  CAS  PubMed  Google Scholar 

  16. Galderisi U, Cascino A, Giordano A. Antisense oligonucleotides as therapeutic agents. J Cell Physiol. 1999;181:251–7.

    Article  CAS  PubMed  Google Scholar 

  17. Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272:263–7.

    Article  CAS  PubMed  Google Scholar 

  18. Naderi M, Abdul TH, Soleimani M, Shabani I, Hashemi SM: A home-brew real-time PCR assay for reliable detection and quantification of mature miR-122. Appl Immunohistochem Mol Morphol 2014.

  19. Samimi H, Zaki dizaji M, Ghadami M, Shahzadeh fazeli A, Khashayar P, Soleimani M, et al. Essential genes in thyroid cancers: focus on fascin. J Diabetes MetabDisord. 2013;12:32.

    Google Scholar 

  20. Kang HY. MicroRNA-21 regulates stemness in cancer cells. Stem Cell Res Ther. 2013;4:110–3.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Schweppe RE, Klopper JP, Korch C, Pugazhenthi U, Benezra M, Knauf JA, et al. Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J Clin Endocrinol Metab. 2008;93:4331–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Meireles AM, Preto A, Rocha AS, Rebocho AP, Máximo V, Pereira-Castro I, et al. Molecular and genotypic characterization of human thyroid follicular cell carcinoma-derived cell lines. Thyroid. 2007;17:707–15.

    Article  CAS  PubMed  Google Scholar 

  23. Pilli T, Prasad KV, Jayarama S, Pacini F, Prabhakar BS. Potential utility and limitations of thyroid cancer cell lines as models for studying thyroid cancer. Thyroid. 2009;19:1333–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Altmann A, Markert A, Askoxylakis V, Schöning T, Jesenofsky R, Eisenhut M, et al. Antitumor effects of proteasome inhibition in anaplastic thyroid carcinoma. J Nucl Med. 2012;53:1764–71.

    Article  CAS  PubMed  Google Scholar 

  25. Thomas T, Nowka K, Lan L, Derwahl M. Expression of endoderm stem cell markers: evidence for the presence of adult stem cells in human thyroid glands. Thyroid. 2006;16:537–44.

    Article  CAS  PubMed  Google Scholar 

  26. Niwa H, Miyazaki J-I, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 2000;24:372–6.

    Article  CAS  PubMed  Google Scholar 

  27. Zheng X, Cui D, Xu S, Brabant G, Derwahl M. Doxorubicin fails to eradicate cancer stem cells derived from anaplastic thyroid carcinoma cells: characterization of resistant cells. Int J Oncol. 2010;37:307–15.

    Article  CAS  PubMed  Google Scholar 

  28. Fierabracci A. Identifying thyroid stem/progenitor cells: advances and limitations. J Endocrinol. 2012;213:1–13.

    Article  CAS  PubMed  Google Scholar 

  29. Kogai T, Taki K, Brent G. Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. Endocr Relat Cancer. 2006;13:797–826.

    Article  CAS  PubMed  Google Scholar 

  30. Lan L, Cui D, Nowka K, Derwahl M. Stem cells derived from goiters in adults form spheres in response to intense growth stimulation and require thyrotropin for differentiation into thyrocytes. J Clin Endocrinol Metab. 2007;92:3681–8.

    Article  CAS  PubMed  Google Scholar 

  31. Lankat-Buttgereit B, Göke R. Programmed cell death protein 4 (pdcd4): a novel target for antineoplastic therapy? Biol Cell. 2003;95:515–9.

    Article  CAS  PubMed  Google Scholar 

  32. Asangani I, Rasheed S, Nikolova D, Leupold J, Colburn N, Post S, et al. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27:2128–36.

    Article  CAS  PubMed  Google Scholar 

  33. Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F, et al. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev. 2003;17:1475–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fernald K, Kurokawa M. Evading apoptosis in cancer. Trends Cell Biol. 2013;23:620–33.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Stiles B, Groszer M, Wang S, Jiao J, Wu H. PTENless means more. Dev Biol. 2004;273:175–84.

    Article  CAS  PubMed  Google Scholar 

  36. Fata JE, Debnath S, Jenkins EC, Fournier MV. Nongenomic mechanisms of PTEN regulation. Int J Cell Biol. 2012;2012:379685.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Buscaglia L, Li Y. Apoptosis and the target genes of microRNA-21. Chin J Cancer. 2011;30:371–80.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9:400–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Smallridge RC, Marlow LA, Copland JA. Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer. 2009;16:17–44.

    Article  CAS  PubMed  Google Scholar 

  40. Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F, et al. Sorafenib inhibits intracellular signaling pathways and induces cell cycle arrest and cell death in thyroid carcinoma cells irrespective of histological origin or BRAF mutational status. BMC Cancer. 2015;15:184.

    Article  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Stem Cell Technology Research Center and Nuclear Medicine Research Center at Shariati Hospital which supported some parts of the experiments. The authors would like to acknowledge the assistance of Dr. Marzieh Ebrahimi, Dr. Mahin Nikogoftar, Dr. Amir Atashi, Mr. Mohsen Malehmir, and Mr. Majid Zakidizaji for their scientific advice and Dr. Mohsen Khorashadizadeh, Dr. Navid Madani, Prof. Anooshirvan Hedayat, Mr. Ehsan Janzamin, Mr. Fazel Samani, and Ms. Azadeh Anbarlou for their technical advice and support.

Funding

This project has been funded by National Elite Foundation of Allameh Tabatabai grant (BN012) and Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences.

Conflicts of interest

None

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Author information

Authors and Affiliations

  1. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Dr. Shariati Hospital, North Kargar Ave., Tehran, 14114, Iran

    Vahid Haghpanah, Hilda Samimi & Bagher Larijani

  2. Department of Laboratory Science, Faculty of Allied Medicine, Alborz University of Medical Sciences, Karaj, Iran

    Parviz Fallah

  3. Department of Molecular Biology and Genetic Engineering, Stem Cell Technology Research Center, Tehran, Iran

    Rezvan Tavakoli & Mahmood Naderi

  4. Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran

    Mahmood Naderi

  5. Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran

    Masoud Soleimani

Authors
  1. Vahid Haghpanah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Parviz Fallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rezvan Tavakoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mahmood Naderi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hilda Samimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masoud Soleimani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bagher Larijani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bagher Larijani.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Haghpanah, V., Fallah, P., Tavakoli, R. et al. Antisense-miR-21 enhances differentiation/apoptosis and reduces cancer stemness state on anaplastic thyroid cancer. Tumor Biol. 37, 1299–1308 (2016). https://doi.org/10.1007/s13277-015-3923-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3923-z

Keywords

Search

Navigation