CTNNA3 is a Tumor Suppressor in Hepatocellular Carcinomas and is Inhibited by MiR-425

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Feb 17

PMID 26882563

Citations 27

Authors

Bing He

Ting Li

Lei Guan

Fang-E Liu

Xue-Mei Chen

Jing Zhao

Song Lin

Zhi-Zhen Liu

Hu-Qin Zhang

Affiliations

Soon will be listed here.

Abstract

Hepatocellular carcinoma (HCC) is a common and leading cause of death worldwide. Here, we identified that a cell-cell adhesion gene, CTNNA3, is a tumor suppressor in HCC. CTNNA3 inhibited the proliferation, migration and invasion of HCC cell lines. In these cells, CTNNA3 inhibited Akt signal, and in turn decreased the proliferating cell nuclear antigen (PCNA) and the matrix metallopeptidase MMP-9, and increased the cell cycle inhibitor p21(Cip1/Waf1). Meanwhile, CTNNA3 is inhibited by miR-425 in HCC. The miR-425 directly bound to the 3'UTR of CTNNA3 and inhibited its expression. The tumor suppressor function of CTNNA3 and the oncogenic function of miR-425 were further confirmed in HCC cell xenograft in nude mice. The miR-425/CTNNA3 axis may provide insights into the mechanisms underlying HCC, and contribute to potential therapeutic strategy of HCC.

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References

Gao G, Kasperbauer J, Tombers N, Cornell M, Smith D . Prognostic significance of decreased expression of six large common fragile site genes in oropharyngeal squamous cell carcinomas. Transl Oncol. 2014; 7(6):726-31. PMC: 4311028. DOI: 10.1016/j.tranon.2014.09.009. View

Fanjul-Fernandez M, Quesada V, Cabanillas R, Cadinanos J, Fontanil T, Obaya A . Cell-cell adhesion genes CTNNA2 and CTNNA3 are tumour suppressors frequently mutated in laryngeal carcinomas. Nat Commun. 2013; 4:2531. DOI: 10.1038/ncomms3531. View

John B, Enright A, Aravin A, Tuschl T, Sander C, Marks D . Human MicroRNA targets. PLoS Biol. 2004; 2(11):e363. PMC: 521178. DOI: 10.1371/journal.pbio.0020363. View

Perez-Moreno M, Jamora C, Fuchs E . Sticky business: orchestrating cellular signals at adherens junctions. Cell. 2003; 112(4):535-48. DOI: 10.1016/s0092-8674(03)00108-9. View

Ji H, Wang J, Fang B, Fang X, Lu Z . α-Catenin inhibits glioma cell migration, invasion, and proliferation by suppression of β-catenin transactivation. J Neurooncol. 2010; 103(3):445-51. DOI: 10.1007/s11060-010-0413-4. View

Kasprzyk A, Keefe D, Smedley D, London D, Spooner W, Melsopp C . EnsMart: a generic system for fast and flexible access to biological data. Genome Res. 2004; 14(1):160-9. PMC: 314293. DOI: 10.1101/gr.1645104. View

Chaffer C, Weinberg R . A perspective on cancer cell metastasis. Science. 2011; 331(6024):1559-64. DOI: 10.1126/science.1203543. View

Majewski I, Kluijt I, Cats A, Scerri T, de Jong D, Kluin R . An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer. J Pathol. 2012; 229(4):621-9. DOI: 10.1002/path.4152. View

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View

10.

Liu T, Zhang X, Sha K, Liu X, Zhang L, Wang B . miR-709 up-regulated in hepatocellular carcinoma, promotes proliferation and invasion by targeting GPC5. Cell Prolif. 2015; 48(3):330-7. PMC: 6495981. DOI: 10.1111/cpr.12181. View

11.

Kim J, Noh E, Kim M, Hwang J, Hwang H, Ryu D . Decursin prevents TPA-induced invasion through suppression of PKCα/p38/NF-κB-dependent MMP-9 expression in MCF-7 human breast carcinoma cells. Int J Oncol. 2014; 44(5):1607-13. DOI: 10.3892/ijo.2014.2327. View

12.

Suzuki H, Katsura A, Matsuyama H, Miyazono K . MicroRNA regulons in tumor microenvironment. Oncogene. 2014; 34(24):3085-94. PMC: 4761641. DOI: 10.1038/onc.2014.254. View

13.

Janku F, Kaseb A, Tsimberidou A, Wolff R, Kurzrock R . Identification of novel therapeutic targets in the PI3K/AKT/mTOR pathway in hepatocellular carcinoma using targeted next generation sequencing. Oncotarget. 2014; 5(10):3012-22. PMC: 4102787. DOI: 10.18632/oncotarget.1687. View

14.

Chuang K, Whitney-Miller C, Chu C, Zhou Z, Dokus M, Schmit S . MicroRNA-494 is a master epigenetic regulator of multiple invasion-suppressor microRNAs by targeting ten eleven translocation 1 in invasive human hepatocellular carcinoma tumors. Hepatology. 2015; 62(2):466-80. PMC: 4682466. DOI: 10.1002/hep.27816. View

15.

Meehan M, Melvin A, Gallagher E, Smith J, McGoldrick A, Moss C . Alpha-T-catenin (CTNNA3) displays tumour specific monoallelic expression in urothelial carcinoma of the bladder. Genes Chromosomes Cancer. 2007; 46(6):587-93. DOI: 10.1002/gcc.20443. View

16.

Bruix J, Gores G, Mazzaferro V . Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014; 63(5):844-55. PMC: 4337888. DOI: 10.1136/gutjnl-2013-306627. View

17.

Bajpai S, Feng Y, Krishnamurthy R, Longmore G, Wirtz D . Loss of alpha-catenin decreases the strength of single E-cadherin bonds between human cancer cells. J Biol Chem. 2009; 284(27):18252-9. PMC: 2709389. DOI: 10.1074/jbc.M109.000661. View

18.

Flores A, Marrero J . Emerging trends in hepatocellular carcinoma: focus on diagnosis and therapeutics. Clin Med Insights Oncol. 2014; 8:71-6. PMC: 4039215. DOI: 10.4137/CMO.S9926. View

19.

Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez J, Zhou D . Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell. 2011; 144(5):782-95. PMC: 3237196. DOI: 10.1016/j.cell.2011.02.031. View

20.

Gao Y, Guan Z, Chen J, Xie H, Yang Z, Fan J . CXCL5/CXCR2 axis promotes bladder cancer cell migration and invasion by activating PI3K/AKT-induced upregulation of MMP2/MMP9. Int J Oncol. 2015; 47(2):690-700. DOI: 10.3892/ijo.2015.3041. View