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Human Cell

pp 1–9 | Cite as

miR-501 acts as an independent prognostic factor that promotes the epithelial–mesenchymal transition through targeting JDP2 in hepatocellular carcinoma

  • Weixuan Yu
  • Wen Deng
  • Qiang Zhao
  • Hongkai Zhuang
  • Chuanzhao ZhangEmail author
  • Zhixiang JianEmail author
Research Article
  • 33 Downloads

Abstract

Hepatocellular carcinoma (HCC), the second common cancer, was a kind of primary liver cancer with high incidence. miR-501, identified as a novel regulator, was acted as a potential biomarker in several diseases. JDP2, acted as a repressor of AP-1 complex, was a member of the basic leucine zipper (bZIP) transcription factor family. RT-qPCR was applied to evaluate miR-501 and JDP2 expression level and we found that miR-501 was upregulated in HCC tissues and cells. miR-501 ectopic expression promoted HCC cell invasion and epithelial–mesenchymal transition (EMT), while low expression present the opposite results. JDP2 was downregulated in HCC tissues and cells, and overexpressed JDP2 facilitated HCC cell invasion and EMT. Furthermore, luciferase reporter assay indicated that JDP2 was a target of miR-501 and altered miR-501 expression the JPD2 mRNA may changed. The expression of miR-501 and JDP2 had negative connection in HCC tissues. In addition, Kaplan–Meier method revealed that miR-501 upregulation or JDP2 downregulation predicted poor prognosis in HCC patients. miR-501 promoted cell invasion and EMT by regulated JDP2 in hepatocellular carcinoma. The newly identified miR-501/JDP2 axis provides novel insight into the pathogenesis of hepatocellular carcinoma.

Keywords

MiR-501 EMT Prognosis Hepatocellular carcinoma 

Notes

Author contributions

CZ and ZJ as the co-corresponding author contributed to the conception of the study and contributed significantly to analyses; WY as the first authorship performed the data and wrote the manuscript; WD as the second author contributed to analyses; QZ as the third author helped perform the analysis with constructive discussions; HZ as the fourth author contributed to the manuscript preparation. All authors read and approved the final manuscript.

Funding

This study was supported by National Natural Science Foundation of China (project no.: 81702783) and The Natural Science Foundation of Guangdong Province (project no.: 2017A030310574).

Compliance with ethical standards

Conflict of interest

All authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Ethics approval and consent to participate

Ethics Committee of Guangdong General Hospital approved the research, and written informed consent was given by all participants.

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Yang JD, Roberts LR. Epidemiology and management of hepatocellular carcinoma. Infect Dis Clin N Am. 2010;24:899–919 (viii).CrossRefGoogle Scholar
  3. 3.
    El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139:817–23.CrossRefPubMedGoogle Scholar
  4. 4.
    Ye QH, Qin LX, Forgues M, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9:416–23.CrossRefPubMedGoogle Scholar
  5. 5.
    Gan W, Huang JL, Zhang MX, et al. New nomogram predicts the recurrence of hepatocellular carcinoma in patients with negative preoperative serum AFP subjected to curative resection. J Surg Oncol. 2018;117(7):1540–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.CrossRefPubMedGoogle Scholar
  8. 8.
    Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. 294. New York: Science; 2001. pp. 853–8.Google Scholar
  9. 9.
    Mizbani A, Luca E, Rushing EJ, Krutzfeldt J. MicroRNA deep sequencing in two adult stem cell populations identifies miR-501 as a novel regulator of myosin heavy chain during muscle regeneration. Development. 2016;143:4137–48.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Liu Y, Chai Y, Zhang J, Tang J. A function variant at miR-501 alters susceptibility to hepatocellular carcinoma in a Chinese Han population. Cell Physiol Biochem. 2016; 38:2500–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Chen S, Zhou YC, Chen Y, et al. Expression profile of miR-501-5p in lung adenocarcinoma patients from Xuanwei area. Nan Fang Yi Ke Da Xue Xue Bao (J South Med Univ). 2017;37:354–59.Google Scholar
  12. 12.
    Hara N, Kikuchi M, Miyashita A, et al. Serum microRNA miR-501-3p as a potential biomarker related to the progression of Alzheimer’s disease. Acta Neuropathol Commun. 2017;5:10.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Fan D, Ren B, Yang X, Liu J, Zhang Z. Upregulation of miR-501-5p activates the wnt/beta-catenin signaling pathway and enhances stem cell-like phenotype in gastric cancer. J Exp Clin Cancer Res CR. 2016;35:177.CrossRefPubMedGoogle Scholar
  14. 14.
    Sanches JGP, Xu Y, Yabasin IB, et al. miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD. Chemico-biol Interact. 2018;285:85–95.CrossRefGoogle Scholar
  15. 15.
    Jin C, Li H, Murata T, et al. JDP2, a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic acid-induced differentiation of F9 cells. Mol Cell Biol. 2002;22:4815–26.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Huang YC, Saito S, Yokoyama KK. Histone chaperone Jun dimerization protein 2 (JDP2): role in cellular senescence and aging. Kaohsiung J Med Sci. 2010;26:515–31.CrossRefPubMedGoogle Scholar
  17. 17.
    Katz S, Heinrich R, Aronheim A. The AP-1 repressor, JDP2, is a bona fide substrate for the c-Jun N-terminal kinase. FEBS Lett. 2001;506:196–200.CrossRefPubMedGoogle Scholar
  18. 18.
    Heinrich R, Livne E, Ben-Izhak O, Aronheim A. The c-Jun dimerization protein 2 inhibits cell transformation and acts as a tumor suppressor gene. J Biol Chem. 2004;279:5708–15.CrossRefPubMedGoogle Scholar
  19. 19.
    van der Weyden L, Rust AG, McIntyre RE, et al. Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity. Oncogene. 2013;32:397–402.CrossRefPubMedGoogle Scholar
  20. 20.
    Rasmussen MH, Wang B, Wabl M, Nielsen AL, Pedersen FS. Activation of alternative Jdp2 promoters and functional protein isoforms in T-cell lymphomas by retroviral insertion mutagenesis. Nucleic Acids Res. 2009;37:4657–71.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Xu Y, Liu Z, Guo K. The effect of JDP2 and ATF2 on the epithelial-mesenchymal transition of human pancreatic cancer cell lines. Pathol Oncol Res POR. 2012;18:571–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Yuanhong X, Feng X, Qingchang L, Jianpeng F, Zhe L, Kejian G. Downregulation of AP-1 repressor JDP2 is associated with tumor metastasis and poor prognosis in patients with pancreatic carcinoma. Int J Biol Markers. 2010;25:136–40.CrossRefPubMedGoogle Scholar
  23. 23.
    Liu Z, Du R, Long J, et al. JDP2 inhibits the epithelial-to-mesenchymal transition in pancreatic cancer BxPC3 cells. Tumour Biol. 2012;33:1527–34.CrossRefPubMedGoogle Scholar
  24. 24.
    Chen YL, Chan SH, Lin PY, Chu PY. The expression of a tumor suppressor gene JDP2 and its prognostic value in hepatocellular carcinoma patients. Hum Pathol. 2017;63:212–16.CrossRefPubMedGoogle Scholar
  25. 25.
    Huang DH, Wang GY, Zhang JW, Li Y, Zeng XC, Jiang N. MiR-501-5p regulates CYLD expression and promotes cell proliferation in human hepatocellular carcinoma. Jpn J Clin Oncol. 2015;45:738–44.CrossRefPubMedGoogle Scholar
  26. 26.
    Ling Q, Xu X, Ye P, et al. The prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma. Oncotarget. 2017;8:15159–67.PubMedPubMedCentralGoogle Scholar

Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Surgical OncologyTungwah Hospital of Sun Yat-Sen UniversityDongguanChina
  2. 2.Biotherapy DepartmentSun Yat-sen Memorial HospitalGuangzhouChina
  3. 3.Organ Transplant Center, The First Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
  4. 4.Department of General Surgery, Guangdong General HospitalGuangdong Academy of Medical SciencesGuangzhouChina

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