Knockdown of circPUM1 impedes cell growth, metastasis and glycolysis of papillary thyroid cancer via enhancing MAPK1 expression by serving as the sponge of miR-21-5p

Abstract

Background

Circular RNAs (circRNAs) are a crucial class of regulatory RNAs in cancer procession, including papillary thyroid cancer (PTC). Circ-Pumilio 1 (circPUM1) is a novel circRNA with the oncogenic function in ovarian cancer and lung cancer. However, the role of circPUM1 in PTC is undiscovered.

Objective

This study was performed to investigate the biological function and molecular mechanism of circPUM1 in PTC.

Methods

CircPUM1 and microRNA-21-5p (miR-21-5p) levels were analyzed via quantitative real-time polymerase chain reaction (qRT-PCR). Cellular viability and metastasis were measured using Cell Counting Kit 8 (CCK-8) and transwell migration/invasion assay. Glycolysis was evaluated by glucose uptake and lactate production. Associated proteins were examined applying with western blot. Dual-luciferase reporter assay and RNA pull-down assay were used to analyze the interaction between circPUM1 or mitogen-activated protein kinase 1 (MAPK1) and miR-21-5p. Moreover, the role of circPUM1 in vivo was explored by xenograft tumor experiment.

Results

Significantly, circPUM1 was upregulated in PTC tissue samples and cells. Cell growth, metastasis and glycolytic process of PTC cells were all inhibited after downregulation of circPUM1. Besides, circPUM1 could sponge miR-21-5p and MAPK1 was a target gene of miR-21-5p. Furthermore, we found that the anti-cancer effect of circPUM1 knockdown on PTC was partly ascribed to MAPK1 downregulation by upregulating miR-21-5p. Silencing circPUM1 also impeded tumorigenesis of PTC in vivo via miR-21-5p/MAPK1 axis.

Conclusion

These findings suggested that circPUM1 knockdown inhibited MAPK1 expression by targeting miR-21-5p, consequently leading to the repressive effect on PTC progression. CircPUM1 might be a promising target to improve the diagnosis and treatment of PTC.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Abbreviations

PTC:

Papillary thyroid cancer

CCK-8:

Cell Counting Kit 8

circPUM1:

Circ-Pumilio 1

MAPK1:

Mitogen-activated protein kinase 1

References

  1. Abdullah MI, Junit SM, Ng KL, Jayapalan JJ, Karikalan B, Hashim OH (2019) Papillary thyroid cancer: genetic alterations and molecular biomarker investigations. Int J Med Sci 16:450–460

    CAS  Article  Google Scholar 

  2. 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

    CAS  Article  Google Scholar 

  3. Braicu C, Zimta AA, Harangus A, Iurca I, Irimie A, Coza O, Berindan-Neagoe I (2019) The function of non-coding RNAs in lung cancer tumorigenesis. Cancers (Basel) 11:605

    CAS  Article  Google Scholar 

  4. Chen J, Xu S, Chen S, Zong Z, Han X, Zhao Y, Shang H (2019a) CircPUM1 promotes the malignant behavior of lung adenocarcinoma by regulating miR-326. Biochem Biophys Res Commun 508:844–849

    CAS  Article  Google Scholar 

  5. Chen L, Nan A, Zhang N, Jia Y, Li X, Ling Y, Dai J, Zhang S, Yang Q, Yi Y et al (2019b) Circular RNA 100146 functions as an oncogene through direct binding to miR-361-3p and miR-615-5p in non-small cell lung cancer. Mol Cancer 18:13

    Article  Google Scholar 

  6. Chen J, Zhong Y, Li L (2020) miR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC). J Transl Med 18:69

    CAS  Article  Google Scholar 

  7. Diao L, Wang S, Sun Z (2018) Long noncoding RNA GAPLINC promotes gastric cancer cell proliferation by acting as a molecular sponge of miR-378 to modulate MAPK1 expression. Onco Targets Ther 11:2797–2804

    Article  Google Scholar 

  8. Guan X, Zong ZH, Liu Y, Chen S, Wang LL, Zhao Y (2019) circPUM1 promotes tumorigenesis and progression of ovarian cancer by sponging miR-615-5p and miR-6753-5p. Mol Ther Nucl Acids 18:882–892

    CAS  Article  Google Scholar 

  9. Hammond SM (2015) An overview of microRNAs. Adv Drug Deliv Rev 87:3–14

    CAS  Article  Google Scholar 

  10. Jin Y, Yu LL, Zhang B, Liu CF, Chen Y (2018) Circular RNA hsa_circ_0000523 regulates the proliferation and apoptosis of colorectal cancer cells as miRNA sponge. Braz J Med Biol Res 51:e7811

    CAS  Article  Google Scholar 

  11. Lan X, Xu J, Chen C, Zheng C, Wang J, Cao J, Zhu X, Ge M (2018) The landscape of circular RNA expression profiles in papillary thyroid carcinoma based on RNA sequencing. Cell Physiol Biochem 47:1122–1132

    CAS  Article  Google Scholar 

  12. Liu C, Bordeaux A, Hettich S, Han S (2020) MicroRNA-497-5p functions as a modulator of apoptosis by regulating metadherin in ovarian cancer. Cell Transplant 29:963689719897061

    PubMed  Google Scholar 

  13. Long X, Shi Y, Ye P, Guo J, Zhou Q, Tang Y (2019) MicroRNA-99a suppresses breast cancer progression by targeting FGFR3. Front Oncol 9:1473

    Article  Google Scholar 

  14. Qian W, Huang T, Feng W (2020) Circular RNA HIPK3 promotes EMT of cervical cancer through sponging miR-338-3p to up-regulate HIF-1alpha. Cancer Manag Res 12:177–187

    CAS  Article  Google Scholar 

  15. Seib CD, Sosa JA (2019) Evolving understanding of the epidemiology of thyroid cancer. Endocrinol Metab Clin North Am 48:23–35

    Article  Google Scholar 

  16. Sun X, Luo L, Gao Y (2020) Circular RNA PVT1 enhances cell proliferation but inhibits apoptosis through sponging microRNA-149 in epithelial ovarian cancer. J Obstet Gynaecol Res 46:625–635

    CAS  Article  Google Scholar 

  17. Wang X, Qi M (2018) miR-718 is involved in malignancy of papillary thyroid cancer through repression of PDPK1. Pathol Res Pract 214:1787–1793

    CAS  Article  Google Scholar 

  18. Wang H, Ke J, Guo Q, Barnabo Nampoukime KP, Yang P, Ma K (2018a) Long non-coding RNA CRNDE promotes the proliferation, migration and invasion of hepatocellular carcinoma cells through miR-217/MAPK1 axis. J Cell Mol Med 22:5862–5876

    CAS  Article  Google Scholar 

  19. Wang M, Chen B, Ru Z, Cong L (2018b) CircRNA circ-ITCH suppresses papillary thyroid cancer progression through miR-22-3p/CBL/beta-catenin pathway. Biochem Biophys Res Commun 504:283–288

    CAS  Article  Google Scholar 

  20. Wang J, Xiao T, Zhao M (2019) MicroRNA-675 directly targets MAPK1 to suppress the oncogenicity of papillary thyroid cancer and is sponged by long non-coding RNA RMRP. Onco Targets Ther 12:7307–7321

    CAS  Article  Google Scholar 

  21. Wang M, Liao Q, Zou P (2020a) PRKCZ-AS1 promotes the tumorigenesis of lung adenocarcinoma via sponging miR-766-5p to modulate MAPK1. Cancer Biol Ther 21:1–8

    Article  Google Scholar 

  22. Wang N, Lu K, Qu H, Wang H, Chen Y, Shan T, Ge X, Wei Y, Zhou P, Xia J (2020b) CircRBM33 regulates IL-6 to promote gastric cancer progression through targeting miR-149. Biomed Pharmacother 125:109876

    CAS  Article  Google Scholar 

  23. Wei H, Pan L, Tao D, Li R (2018) Circular RNA circZFR contributes to papillary thyroid cancer cell proliferation and invasion by sponging miR-1261 and facilitating C8orf4 expression. Biochem Biophys Res Commun 503:56–61

    CAS  Article  Google Scholar 

  24. Wiltshire JJ, Drake TM, Uttley L, Balasubramanian SP (2016) Systematic review of trends in the incidence rates of thyroid cancer. Thyroid 26:1541–1552

    Article  Google Scholar 

  25. Xu Y, Han YF, Zhu SJ, Dong JD, Ye B (2017) miRNA148a inhibits cell growth of papillary thyroid cancer through STAT3 and PI3K/AKT signaling pathways. Oncol Rep 38:3085–3093

    CAS  Article  Google Scholar 

  26. Ye M, Hou H, Shen M, Dong S, Zhang T (2019) Circular RNA circFOXM1 plays a role in papillary thyroid carcinoma by sponging miR-1179 and regulating HMGB1 expression. Mol Ther Nucl Acids 19:741–750

    Article  Google Scholar 

  27. Yin Y, Long J, He Q, Li Y, Liao Y, He P, Zhu W (2019) Emerging roles of circRNA in formation and progression of cancer. J Cancer 10:5015–5021

    CAS  Article  Google Scholar 

  28. Zhang H, Cai Y, Zheng L, Zhang Z, Lin X, Jiang N (2018) LncRNA BISPR promotes the progression of thyroid papillary carcinoma by regulating miR-21-5p. Int J Immunopathol Pharmacol 32:2058738418772652

    Article  Google Scholar 

  29. Zhao J, Li Z, Chen Y, Zhang S, Guo L, Gao B, Jiang Y, Tian W, Hao S, Zhang X (2019) MicroRNA766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway. Int J Oncol 54:315–325

    CAS  PubMed  Google Scholar 

Download references

Acknowledgement

None.

Funding

None.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Buqiang Wu.

Ethics declarations

Conflict of interest

Yanqi Li, Jun Qin, Zhaocai He, Guang Cui, Kun Zhang and Buqiang Wu declare that they have no conflict of interest.

Ethical approval

This study had been approved by the Ethics Committee of Heping Hospital Affiliated to Changzhi Medical College. Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Qin, J., He, Z. et al. Knockdown of circPUM1 impedes cell growth, metastasis and glycolysis of papillary thyroid cancer via enhancing MAPK1 expression by serving as the sponge of miR-21-5p. Genes Genom 43, 141–150 (2021). https://doi.org/10.1007/s13258-020-01023-6

Download citation

Keywords

  • CircPUM1
  • Papillary thyroid cancer
  • miR-21-5p
  • MAPK1