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.
MiR-501 EMT Prognosis Hepatocellular carcinoma
This is a preview of subscription content, log in to check access.
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.
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.
Yang JD, Roberts LR. Epidemiology and management of hepatocellular carcinoma. Infect Dis Clin N Am. 2010;24:899–919 (viii).CrossRefGoogle Scholar
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
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.CrossRefGoogle Scholar
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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