Skip to main content
SpringerLink
Log in

microRNA-181a promotes the oncogene S100A2 and enhances papillary thyroid carcinoma growth by mediating the expression of histone demethylase KDM5C

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Background and purpose

Papillary thyroid carcinoma (PTC) is an endocrine malignancy. Increasing evidence highlights microRNAs (miRNAs) as important participants in PTC. Here, we investigated the role of miR-181a in PTC.

Methods

A microarray-based analysis was performed to identify the differential expression of miR-181a in PTC, which was validated with RT-qPCR. Protein expression of the proliferation-related factor Ki-67 and apoptosis- and migration-related factors in PTC was assessed with immunoblot analysis. A dual-luciferase reporter gene assay was adopted to verify the relationship between miR-181a and lysine demethylase 5C (KDM5C). Chromatin immunoprecipitation (ChIP) was used to detect the level of the H3K4me3 modification on S100 calcium-binding protein A2 (S100A2). Cell viability, apoptosis, and invasion and migration abilities were evaluated by Cell Counting Kit-8 (CCK-8), flow cytometry, and transwell assays, respectively. The in vitro results were verified in in vivo nude mouse models.

Results

miR-181a was highly expressed in PTC tissues and cell lines. Silencing miR-181a repressed the proliferation and migration of PTC cells. KDM5C was identified as the target gene of miR-181a and represses S100A2 expression through histone demethylation to diminish the migration and proliferation of PTC cells. miR-181a depletion suppressed tumor growth.

Conclusion

Collectively, these results suggest that highly expressed miR-181a promotes the proliferation of PTC cells by increasing the expression of the oncogene S100A2. This study contributes to the advancement of miR-181a-targeted therapeutics.

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. Liu T, You X, Sui J, Shen B, Zhang Y, Zhang XM, Yang S, Yao YZ, Yang F, Yin LH, Pu YP, Liang GY (2018) Prognostic value of a two-microRNA signature for papillary thyroid cancer and a bioinformatic analysis of their possible functions. J Cell Biochem. https://doi.org/10.1002/jcb.27993

    Article  PubMed  PubMed Central  Google Scholar 

  2. Park H, Park J, Park SY, Kim TH, Kim SW, Chung JH (2020) Clinical course from diagnosis to death in patients with well-differentiated thyroid cancer. Cancers (Basel). https://doi.org/10.3390/cancers12082323

    Article  PubMed Central  Google Scholar 

  3. Ren L, Xu Y, Qin G, Liu C, Yan Y, Zhang H (2019) miR-199b-5p-Stonin 2 axis regulates metastases and epithelial-to-mesenchymal transition of papillary thyroid carcinoma. IUBMB Life 71:28–40. https://doi.org/10.1002/iub.1889

    Article  CAS  PubMed  Google Scholar 

  4. Mohamad Yusof A, Jamal R, Muhammad R, Abdullah Suhaimi SN, Mohamed Rose I, Saidin S, Ab Mutalib NS (2018) Integrated characterization of MicroRNA and mRNA transcriptome in papillary thyroid carcinoma. Front Endocrinol (Lausanne) 9:158. https://doi.org/10.3389/fendo.2018.00158

    Article  Google Scholar 

  5. Guo H, Ingolia NT, Weissman JS, Bartel DP (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466:835–840. https://doi.org/10.1038/nature09267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Di Leva G, Garofalo M, Croce CM (2014) MicroRNAs in cancer. Annu Rev Pathol 9:287–314. https://doi.org/10.1146/annurev-pathol-012513-104715

    Article  CAS  PubMed  Google Scholar 

  7. Chruscik A, Lam AK (2015) Clinical pathological impacts of microRNAs in papillary thyroid carcinoma: a crucial review. Exp Mol Pathol 99:393–398. https://doi.org/10.1016/j.yexmp.2015.08.013

    Article  CAS  PubMed  Google Scholar 

  8. Greer EL, Shi Y (2012) Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 13:343–357. https://doi.org/10.1038/nrg3173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hong Z, Wu G, Xiang ZD, Xu CD, Huang SS, Li C, Shi L, Wu DL (2019) KDM5C is transcriptionally regulated by BRD4 and promotes castration-resistance prostate cancer cell proliferation by repressing PTEN. Biomed Pharmacother 114:108793. https://doi.org/10.1016/j.biopha.2019.108793

    Article  CAS  PubMed  Google Scholar 

  10. Kim Y, Jeong Y, Kwon K, Ismail T, Lee HK, Kim C, Park JW, Kwon OS, Kang BS, Lee DS, Park TJ, Kwon T, Lee HS (2018) Physiological effects of KDM5C on neural crest migration and eye formation during vertebrate development. Epigenetics Chromatin 11:72. https://doi.org/10.1186/s13072-018-0241-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hountis P, Matthaios D, Froudarakis M, Bouros D, Kakolyris S (2014) S100A2 protein and non-small cell lung cancer. The dual role concept Tumour Biol 35:7327–7333. https://doi.org/10.1007/s13277-014-2117-4

    Article  CAS  PubMed  Google Scholar 

  12. Ito Y, Yoshida H, Tomoda C, Uruno T, Miya A, Kobayashi K, Matsuzuka F, Kakudo K, Kuma K, Miyauchi A (2005) Expression of S100A2 and S100A6 in thyroid carcinomas. Histopathology 46:569–575. https://doi.org/10.1111/j.1365-2559.2005.02137.x

    Article  CAS  PubMed  Google Scholar 

  13. Tuo YL, Li XM, Luo J (2015) Long noncoding RNA UCA1 modulates breast cancer cell growth and apoptosis through decreasing tumor suppressive miR-143. Eur Rev Med Pharmacol Sci 19:3403–3411

    PubMed  Google Scholar 

  14. Aragon Han P, Weng CH, Khawaja HT, Nagarajan N, Schneider EB, Umbricht CB, Witwer KW, Zeiger MA (2015) MicroRNA expression and association with clinicopathologic features in papillary thyroid cancer: a systematic review. Thyroid 25:1322–1329. https://doi.org/10.1089/thy.2015.0193

    Article  CAS  PubMed  Google Scholar 

  15. Liu J, Liu Y, Lin Y, Liang J (2019) Radioactive iodine-refractory differentiated thyroid cancer and redifferentiation therapy. Endocrinol Metab (Seoul) 34:215–225. https://doi.org/10.3803/EnM.2019.34.3.215

    Article  CAS  Google Scholar 

  16. Yin X, Zhang J, Li C, Zhang Z, Jin T, Song L, Zhang R, Wang W, Tao Y, Wang X (2019) LncRNA HOXA11-AS accumulation-induced microRNA-761 downregulation regulates cell growth by targeting TRIM29 in papillary thyroid cancer. Am J Transl Res 11:6826–6837

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Liang M, Yu S, Tang S, Bai L, Cheng J, Gu Y, Li S, Zheng X, Duan L, Wang L, Zhang Y, Huang X (2020) A panel of plasma Exosomal miRNAs as potential biomarkers for differential diagnosis of thyroid nodules. Front Genet 11:449. https://doi.org/10.3389/fgene.2020.00449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yang Y, Xia S, Zhang L, Wang W, Chen L, Zhan W (2020) MiR-324-5p/PTPRD/CEBPD axis promotes papillary thyroid carcinoma progression via microenvironment alteration. Cancer Biol Ther 21:522–532. https://doi.org/10.1080/15384047.2020.1736465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chou CK, Liu RT, Kang HY (2017) MicroRNA-146b: a novel biomarker and therapeutic target for human papillary thyroid cancer. Int J Mol Sci. https://doi.org/10.3390/ijms18030636

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hajsl M, Hlavackova A, Broulikova K, Sramek M, Maly M, Dyr JE, Suttnar J (2020) Tryptophan metabolism, inflammation, and oxidative stress in patients with neurovascular disease. Metabolites. https://doi.org/10.3390/metabo10050208

    Article  PubMed  PubMed Central  Google Scholar 

  21. Saberinia A, Alinezhad A, Jafari F, Soltany S, Akhavan Sigari R (2020) Oncogenic miRNAs and target therapies in colorectal cancer. Clin Chim Acta 508:77–91. https://doi.org/10.1016/j.cca.2020.05.012

    Article  CAS  PubMed  Google Scholar 

  22. Sokolowska J, Urbanska K (2019) Immunohistochemical assessment of metalloproteinases MMP2 and MMP9 expression in canine various subtypes of lymphomas in relation with proliferative and apoptotic markers. Pol J Vet Sci 22:203–211. https://doi.org/10.24425/pjvs.2019.127087

    Article  CAS  PubMed  Google Scholar 

  23. Park JK, Park SH, So K, Bae IH, Yoo YD, Um HD (2010) ICAM-3 enhances the migratory and invasive potential of human non-small cell lung cancer cells by inducing MMP-2 and MMP-9 via Akt and CREB. Int J Oncol 36:181–192

    CAS  PubMed  Google Scholar 

  24. Tan AS, Yeong JPS, Lai CPT, Ong CHC, Lee B, Lim JCT, Thike AA, Iqbal J, Dent RA, Lim EH, Tan PH (2019) The role of Ki-67 in Asian triple negative breast cancers: a novel combinatory panel approach. Virchows Arch 475:709–725. https://doi.org/10.1007/s00428-019-02635-4

    Article  CAS  PubMed  Google Scholar 

  25. Jin C, Miao X, Zhong Y, Han J, Liu Q, Zhu J, Xia X, Peng X (2020) The renoprotective effect of diosgenin on aristolochic acid I-induced renal injury in rats: impact on apoptosis, mitochondrial dynamics and autophagy. Food Funct. https://doi.org/10.1039/d0fo00401d

    Article  PubMed  Google Scholar 

  26. Zhang X, Nie Y, Du Y, Cao J, Shen B, Li Y (2012) MicroRNA-181a promotes gastric cancer by negatively regulating tumor suppressor KLF6. Tumour Biol 33:1589–1597. https://doi.org/10.1007/s13277-012-0414-3

    Article  CAS  PubMed  Google Scholar 

  27. Zang X, Li Q, Wang W, Zhou Y, Chen S, Xiao T (2016) miR-181a promotes the proliferation and metastasis of osteosarcoma cells by targeting RASSF1A. Zhong Nan Da Xue Xue Bao Yi Xue Ban 41:789–795. https://doi.org/10.11817/j.issn.1672-7347.2016.08.003

    Article  PubMed  Google Scholar 

  28. Hu P, Zhou L, Wang C, Cao G, Chang Y (2020) MiR-181a reduces radiosensitivity of non-small cell lung cancer via inhibiting PTEN. Panminerva Med. https://doi.org/10.23736/S0031-0808.20.03976-2

    Article  PubMed  Google Scholar 

  29. Li C, Wu B, Han H, Zhao J, Bai Y, Liu X (2020) Identification of MicroRNA-related tumorigenesis variants and genes in the cancer genome atlas (TCGA) data. Genes (Basel). https://doi.org/10.3390/genes11090953

    Article  PubMed  PubMed Central  Google Scholar 

  30. Dutta A, Choudhary P, Caruana J, Raina R (2017) JMJ27, an Arabidopsis H3K9 histone demethylase, modulates defense against Pseudomonas syringae and flowering time. Plant J 91:1015–1028. https://doi.org/10.1111/tpj.13623

    Article  CAS  PubMed  Google Scholar 

  31. Nicolson NG, Murtha TD, Dong W, Paulsson JO, Choi J, Barbieri AL, Brown TC, Kunstman JW, Larsson C, Prasad ML, Korah R, Lifton RP, Juhlin CC, Carling T (2018) Comprehensive genetic analysis of follicular thyroid carcinoma predicts prognosis independent of histology. J Clin Endocrinol Metab 103:2640–2650. https://doi.org/10.1210/jc.2018-00277

    Article  PubMed  Google Scholar 

  32. Chang S, Yim S, Park H (2019) The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Exp Mol Med 51:1–17. https://doi.org/10.1038/s12276-019-0230-6

    Article  CAS  PubMed  Google Scholar 

  33. Zhang B, Zhou BH, Xiao M, Li H, Guo L, Wang MX, Yu SH, Ye QH (2020) KDM5C represses FASN-mediated lipid metabolism to exert tumor suppressor activity in intrahepatic cholangiocarcinoma. Front Oncol 10:1025. https://doi.org/10.3389/fonc.2020.01025

    Article  PubMed  PubMed Central  Google Scholar 

  34. Pan SC, Li CY, Kuo CY, Kuo YZ, Fang WY, Huang YH, Hsieh TC, Kao HY, Kuo Y, Kang YR, Tsai WC, Tsai ST, Wu LW (2018) The p53–S100A2 positive feedback loop negatively regulates epithelialization in cutaneous wound healing. Sci Rep 8:5458. https://doi.org/10.1038/s41598-018-23697-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shen H, Xu W, Guo R, Rong B, Gu L, Wang Z, He C, Zheng L, Hu X, Hu Z, Shao ZM, Yang P, Wu F, Shi YG, Shi Y, Lan F (2016) Suppression of enhancer overactivation by a RACK7-histone demethylase complex. Cell 165:331–342. https://doi.org/10.1016/j.cell.2016.02.064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li C, Chen Q, Zhou Y, Niu Y, Wang X, Li X, Zheng H, Wei T, Zhao L, Gao H (2020) S100A2 promotes glycolysis and proliferation via GLUT1 regulation in colorectal cancer. FASEB J. https://doi.org/10.1096/fj.202000555R

    Article  PubMed  Google Scholar 

  37. Naz S, Bashir M, Ranganathan P, Bodapati P, Santosh V, Kondaiah P (2014) Protumorigenic actions of S100A2 involve regulation of PI3/Akt signaling and functional interaction with Smad3. Carcinogenesis 35:14–23. https://doi.org/10.1093/carcin/bgt287

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81402213) and Characteristic Innovation Projects of General Colleges and Universities in Guangdong Province (Grant No. 2019KTSCX009) award to Yingxue Wang, the National Natural Science Foundation of China (Grant No. 81874220), and Guangdong Basic and Applied Basic Research Foundation (Grant No. 2020A151501030) award to Lei Zhao.

Author information

Authors and Affiliations

  1. Department of Endocrinology, the First Affiliated Hospital of Jinan University, No. 613, West Huangpu Avenue, Tianhe District, Guangzhou, 510630, Guangdong Province, People’s Republic of China

    Y. Wang, J. Li & A. Cen

  2. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Hepatopancreatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    H. Ye

  3. Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

    Y. Yang & L. Zhao

Authors
  1. Y. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Cen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YW and LZ designed the study. HY, AC and JL collated the data, carried out data analyses and produced the initial draft of the manuscript. YY and JL contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

Corresponding author

Correspondence to Y. Wang.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

The experimental design was approved by the Institutional Research Ethics Committee of Sun Yat-sen University Cancer Center (Guangzhou, China) and conducted in compliance with the Declaration of Helsinki. The experiments involving animals were performed in line with the Guide for the Care and Use of Laboratory Animals to minimize the suffering and discomfort of experimental animals.

Informed consent

All participants involved in this study provided informed written consent.

Additional information

Publisher's Note

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

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Ye, H., Yang, Y. et al. microRNA-181a promotes the oncogene S100A2 and enhances papillary thyroid carcinoma growth by mediating the expression of histone demethylase KDM5C. J Endocrinol Invest 45, 17–28 (2022). https://doi.org/10.1007/s40618-021-01606-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-021-01606-4

Keywords

Search

Navigation