Abstract
Our study aimed to investigate the isoform-specific distribution of 14-3-3 in tongue squamous cell carcinoma (TSCC) and their association with cancer progression, and to further discuss their roles in cancer cell survival. In this study, 42 TSCC specimens and their matched normal para-carcinoma sections were collected. The immunohistochemistry analysis identified that 14-3-3σ and ζ isoforms presented significantly higher expression in cancerous tissues compared with the matched normal tongue tissue sections. 14-3-3ζ expression was associated with tumor T stage, lymph node metastasis and poor prognosis of TSCC. In vitro study revealed that 14-3-3ζ silencing alleviated the proliferation and migration of TSCC cells while promoted cancer cell apoptosis. 14-3-3ζ could bind to and inactivate FOXO3a transcription factor, in turn leading to the movement of the 14-3-3ζ–FOXO3a complex from nucleus to cytoplasm, which was inhibited after 14-3-3ζ silencing. Both 14-3-3ζ and FOXO3a silencing increased caspase 3 and 9 activation, while reduced inner mitochondrial membrane potential. Collectively, 14-3-3ζ may serve as a hallmark and prognostic marker of TSCC. 14-3-3ζ can bind to the FOXO3a transcription factor to promote the export of the complex to the cytoplasm, leading to enhanced proliferation and migration of tongue cancer cells.
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References
Korpi JT, Kervinen V, Mäklin H, Väänänen A, Lahtinen M, Läärä E et al. Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer. Brit J Cancer 2008; 98: 766–775.
Song X, Zhang W, Zhang Y, Zhang H, Fu Z, Ye J et al. Expression of semaphorin 3A and neuropilin 1 with clinicopathological features and survival in human tongue cancer. Med Oral Patol Oral Cir Bucal 2012; 17: e962.
Chang C-C, Yang Y-J, Li Y-J, Chen S-T, Lin B-R, Wu T-S et al. MicroRNA-17/20a functions to inhibit cell migration and can be used a prognostic marker in oral squamous cell carcinoma. Oral Oncol 2013; 49: 923–931.
Mhawech P . 14-3-3 proteins—an update. Cell Res 2005; 15: 228–236.
Freeman AK, Morrison DK . 14-3-3 Proteins: diverse functions in cell proliferation and cancer progression. Semin Cell Dev Biol 2011; 22: 681–687.
Fu H, Subramanian RR, Masters SC . 14-3-3 proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol 2000; 40: 617–647.
Matta A, Bahadur S, Duggal R, Gupta SD, Ralhan R . Over-expression of 14-3-3zeta is an early event in oral cancer. BMC Cancer 2007; 7: 169.
Matta A, Siu KM, Ralhan R . 14-3-3 zeta as novel molecular target for cancer therapy. Exp Opin Therap Target 2012; 16: 515–523.
Laimer K, Blassnig N, Spizzo G, Kloss F, Rasse M, Obrist P et al. Prognostic significance of 14-3-3sigma expression in oral squamous cell carcinoma (OSCC). Oral Oncol 2009; 45: 127–134.
Horie M, Suzuki M, Takahashi E-i, Tanigami A . Cloning, expression, and chromosomal mapping of the human 14-3-3 γ gene (YWHAG) to 7q11. 23. Genomic 1999; 60: 241–243.
Qi W, Liu X, Qiao D, Martinez JD . Isoform-specific expression of 14-3-3 proteins in human lung cancer tissues. Int J Cancer 2005; 113: 359–363.
Hayashi E, Kuramitsu Y, Fujimoto M, Zhang X, Tanaka T, Uchida K et al. Proteomic profiling of differential display analysis for human oral squamous cell carcinoma: 14-3-3 σ Protein is upregulated in human oral squamous cell carcinoma and dependent on the differentiation level. Proteomics Clin Appli 2009; 3: 1338–1347.
Rodriguez LG, Guan JL . 14-3-3 regulation of cell spreading and migration requires a functional amphipathic groove. J Cell Physiol 2005; 202: 285–294.
Liu MY, Cai S, Espejo A, Bedford MT, Walker CL . 14-3-3 interacts with the tumor suppressor tuberin at Akt phosphorylation site (s). Cancer Res 2002; 62: 6475–6480.
Nomura M, Shimizu S, Sugiyama T, Narita M, Ito T, Matsuda H et al. 14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax. J Biol Chem 2003; 278: 2058–2065.
Samuel T, Weber HO, Rauch P, Verdoodt B, Eppel J-T, McShea A et al. The G2/M regulator 14-3-3σ prevents apoptosis through sequestration of Bax. J Biol Chem 2001; 276: 45201–45206.
Wang H, Zhang Z, Li R, Ang KK, Zhang H, Caraway NP et al. Overexpression of S100A2 protein as a prognostic marker for patients with stage I non small cell lung cancer. Int J Cancer 2005; 116: 285–290.
Baljinnyam E, Umemura M, De Lorenzo MS, Xie LH, Nowycky M, Iwatsubo M et al. Gbetagamma subunits inhibit Epac-induced melanoma cell migration. BMC Cancer 2011; 11: 256.
Tzivion G, Dobson M, Ramakrishnan G . FoxO transcription factors; regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta 2011; 1813: 1938–1945.
Obsilova V, Silhan J, Boura E, Teisinger J, Obsil T . 14-3-3 proteins: a family of versatile molecular regulators. Physiol Res 2008; 57 (Suppl 3): S11–S21.
Ralhan R, Masui O, DeSouza LV, Matta A, Macha M, Siu K . Identification of proteins secreted by head and neck cancer cell lines using LC‐MS/ MS: strategy for discovery of candidate serological biomarkers. Proteomics 2011; 11: 2363–2376.
Zhao GY, Ding JY, Gu J, Lu CL, Lin ZW, Guo J et al. The overexpression of 14-3-3ζ and Hsp27 promotes non–small cell lung cancer progression. Cancer 2014; 120: 652–663.
Hatzipetros I, Gocze P, Koszegi T, Jaray A, Szereday L, Polgar B et al. Investigating the clinical potential for 14-3-3 zeta protein to serve as a biomarker for epithelial ovarian cancer. J Ovarian Res 2013; 6: 79.
Fu Z, Tindall DJ . FOXOs, cancer and regulation of apoptosis. Oncogene 2008; 27: 2312–2319.
Arden KC . Multiple roles of FOXO transcription factors in mammalian cells point to multiple roles in cancer. Exp Gerontol 2006; 41: 709–717.
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Jin, L., Han, X., Jie, Y. et al. 14-3-3ζ silencing retards tongue squamous cell carcinoma progression by inhibiting cell survival and migration. Cancer Gene Ther 23, 206–213 (2016). https://doi.org/10.1038/cgt.2016.15
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DOI: https://doi.org/10.1038/cgt.2016.15
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