MiR-214/199a/199a* Cluster Levels Predict Poor Survival in Hepatocellular Carcinoma Through Interference with Cell-cycle Regulators

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Oct 27

PMID 26498144

Citations 15

Authors

Peipei Wang

Song Chen

He Fang

Xiaojuan Wu

Dabiao Chen

Liang Peng

Zhiliang Gao

Chan Xie

Affiliations

Soon will be listed here.

Abstract

Aims: To identify the clinical and functional association of miR-214/199a/199a* cluster in human hepatocellular carcinoma (HCC) and to clarify the mechanism of miR-214.

Methods: Kaplan-Meier and Cox proportional regression analyses were used to determine the association of miR-214/199a/199a* cluster levels with the survival of HCC patients. The role of miR-214 in regulating HCC cell proliferation was studied with miR-214 mimics/inhibitor-treated cells. Furthermore, the inhibition effect of miR-214 on E2F2, cyclin-dependent kinase (CDK) 3 and CDK6 expression was assessed in HCC cell lines with miR-214 mimics/inhibitors to increase/decrease miR-214 expression. Direct binding of miR-214 to the 3'-untranslated regions of E2F2, CDK3, and CDK6 was verified by dual-luciferase reporter assay.

Results: In analyzing HCC clinical specimens and cell lines, we discovered a uniform decrease in miR-214/199a/199a* expression in comparison with noncancerous tissue or normal liver epithelial cell lines. Higher miR-214 levels were related with improved patient survival. Overexpression of miR-214 in HCC cells inhibited proliferation by inducing G1-S checkpoint arrest. Conversely, RNA interference-mediated silencing of miR-214 promoted cell-cycle progression and accelerated the proliferation of HCC cells. E2F2, CDK3 and CDK6 were each directly targeted for inhibition by miR-214, and restoring their expression reversed miR-214 inhibition of cell-cycle progression. The relationship between expression of miR-214 and its targets was confirmed in HCC tumor xenografts and clinical specimens.

Conclusions: Our results demonstrate that miR-214 has tumor-suppressive activity in HCC through inhibition of E2F2, CDK3 and CDK6.

Citing Articles

Retraction Note: Forkhead box (FOX) G1 promotes hepatocellular carcinoma epithelial-Mesenchymal transition by activating Wnt signal through forming T-cell factor-4/Beta-catenin/FOXG1 complex.

Zheng X, Lin J, Wu H, Mo Z, Lian Y, Wang P J Exp Clin Cancer Res. 2023; 42(1):156.

PMID: 37386481 PMC: 10308604. DOI: 10.1186/s13046-023-02739-5.

A review on the role of cyclin dependent kinases in cancers.

Ghafouri-Fard S, Khoshbakht T, Hussen B, Dong P, Gassler N, Taheri M Cancer Cell Int. 2022; 22(1):325.

PMID: 36266723 PMC: 9583502. DOI: 10.1186/s12935-022-02747-z.

MicroRNA-214 enriched exosomes from human cerebral endothelial cells (hCEC) sensitize hepatocellular carcinoma to anti-cancer drugs.

Semaan L, Zeng Q, Lu Y, Zhang Y, Zreik M, Chamseddine M Oncotarget. 2021; 12(3):185-198.

PMID: 33613846 PMC: 7869574. DOI: 10.18632/oncotarget.27879.

The Effect of miR-98 and miR-214 on Apoptotic and Angiogenic Pathways in Hepatocellular Carcinoma HepG2 Cells.

Yahya S, Yahya S Indian J Clin Biochem. 2020; 35(3):353-358.

PMID: 32647414 PMC: 7326845. DOI: 10.1007/s12291-019-00824-1.

Interstitial microRNA miR-214 attenuates inflammation and polycystic kidney disease progression.

Lakhia R, Yheskel M, Flaten A, Ramalingam H, Aboudehen K, Ferre S JCI Insight. 2020; 5(7).

PMID: 32182218 PMC: 7205276. DOI: 10.1172/jci.insight.133785.

References

Chen C, Wells A . Comparative analysis of E2F family member oncogenic activity. PLoS One. 2007; 2(9):e912. PMC: 1975672. DOI: 10.1371/journal.pone.0000912. View

Zou Z, Fan L, Wang L, Xu J, Zhang R, Tian T . miR-26a and miR-214 down-regulate expression of the PTEN gene in chronic lymphocytic leukemia, but not PTEN mutation or promoter methylation. Oncotarget. 2014; 6(2):1276-85. PMC: 4359232. DOI: 10.18632/oncotarget.2626. View

Zhang L, Guo Y, Zhao C, Gao J . Effects and mechanism of miR-214 on hepatocellular carcinoma. Asian Pac J Trop Med. 2015; 8(5):392-8. DOI: 10.1016/S1995-7645(14)60350-3. View

Duan Q, Wang X, Gong W, Ni L, Chen C, He X . ER stress negatively modulates the expression of the miR-199a/214 cluster to regulates tumor survival and progression in human hepatocellular cancer. PLoS One. 2012; 7(2):e31518. PMC: 3281082. DOI: 10.1371/journal.pone.0031518. View

Suriawinata A, Xu R . An update on the molecular genetics of hepatocellular carcinoma. Semin Liver Dis. 2004; 24(1):77-88. DOI: 10.1055/s-2004-823102. View

Jiang J, Gusev Y, Aderca I, Mettler T, Nagorney D, Brackett D . Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res. 2008; 14(2):419-27. PMC: 2755230. DOI: 10.1158/1078-0432.CCR-07-0523. View

Dimova D, Dyson N . The E2F transcriptional network: old acquaintances with new faces. Oncogene. 2005; 24(17):2810-26. DOI: 10.1038/sj.onc.1208612. View

Thorgeirsson S, Grisham J . Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002; 31(4):339-46. DOI: 10.1038/ng0802-339. View

Nelsen C, Rickheim D, Timchenko N, Stanley M, Albrecht J . Transient expression of cyclin D1 is sufficient to promote hepatocyte replication and liver growth in vivo. Cancer Res. 2001; 61(23):8564-8. View

10.

Li B, He H, Tao B, Zhao Z, Hu G, Luo C . Knockdown of CDK6 enhances glioma sensitivity to chemotherapy. Oncol Rep. 2012; 28(3):909-14. DOI: 10.3892/or.2012.1884. View

11.

Santoni-Rugiu E, Jensen M, Thorgeirsson S . Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor alpha. Cancer Res. 1998; 58(1):123-34. View

12.

Fujimoto T, Anderson K, Jacobsen S, Nishikawa S, Nerlov C . Cdk6 blocks myeloid differentiation by interfering with Runx1 DNA binding and Runx1-C/EBPalpha interaction. EMBO J. 2007; 26(9):2361-70. PMC: 1864973. DOI: 10.1038/sj.emboj.7601675. View

13.

Lee J, Heo M, Lee C, Yang Y, Kim S . Increase of miR-199a-5p by protoporphyrin IX, a photocatalyzer, directly inhibits E2F3, sensitizing mesenchymal tumor cells to anti-cancer agents. Oncotarget. 2015; 6(6):3918-31. PMC: 4414163. DOI: 10.18632/oncotarget.2928. View

14.

Zhan L, Huang C, Meng X, Song Y, Wu X, Miu C . Promising roles of mammalian E2Fs in hepatocellular carcinoma. Cell Signal. 2014; 26(5):1075-81. DOI: 10.1016/j.cellsig.2014.01.008. View

15.

Wang J, Li J, Wang X, Zheng C, Ma W . Downregulation of microRNA-214 and overexpression of FGFR-1 contribute to hepatocellular carcinoma metastasis. Biochem Biophys Res Commun. 2013; 439(1):47-53. DOI: 10.1016/j.bbrc.2013.08.032. View

16.

Matsuda Y, Ichida T, Genda T, Yamagiwa S, Aoyagi Y, Asakura H . Loss of p16 contributes to p27 sequestration by cyclin D(1)-cyclin-dependent kinase 4 complexes and poor prognosis in hepatocellular carcinoma. Clin Cancer Res. 2003; 9(9):3389-96. View

17.

Weinberg R . The retinoblastoma protein and cell cycle control. Cell. 1995; 81(3):323-30. DOI: 10.1016/0092-8674(95)90385-2. View

18.

Hanahan D, Weinberg R . The hallmarks of cancer. Cell. 2000; 100(1):57-70. DOI: 10.1016/s0092-8674(00)81683-9. View

19.

Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E . Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest. Mol Cell Biol. 1999; 19(2):1460-9. PMC: 116074. DOI: 10.1128/MCB.19.2.1460. View

20.

Attwooll C, Denchi E, Helin K . The E2F family: specific functions and overlapping interests. EMBO J. 2004; 23(24):4709-16. PMC: 535093. DOI: 10.1038/sj.emboj.7600481. View