Abstract
Objective
Cancer/testis antigen FMR1NB is aberrantly expressed in various types of cancer, but not in normal tissues except for testis. This study aimed to investigate the expression and functional role of FMR1NB in glioma.
Methods
The expression of FMR1NB mRNA and protein was determined using RT-PCR and immunohistochemistry, respectively, in glioma specimens from 83 patients at follow-up. The effects of siRNA-mediated FMR1NB silencing on malignant biological behaviors were evaluated in glioma cell lines A172 and U251.
Results
FMR1NB mRNA and protein expression was detected in 58.8% (77/131) and 46.34% (57/123) of glioma tissues, respectively. FMR1NB protein was positively correlated with World Health Organization grade and found to be an independent prognostic marker for poor outcome. Knockdown of FMR1NB induced apoptosis and suppressed proliferation, adhesion, migration, and invasion by modulating the expression of cyclin A, CDK2, caspase-3, E-cadherin, and N-cadherin in A172 and U251 cells.
Conclusion
Our findings suggest that FMR1NB contributes to the tumorigenesis of glioma cells and may represent a potential prognostic biomarker and an attractive therapeutic target in glioma.
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References
Ostrom QT, Gittleman H, Liao P, et al. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncology, 2017,19(suppl_5):v1–v88
Yang P, Wang Y, Peng X, et al. Management and survival rates in patients with glioma in China (2004–2010): a retrospective study from a single-institution. J Neurooncol, 2013,113(2):259–266
Wang HW, Xu ZK, Song Y, et al. Correlations of MGMT genetic polymorphisms with temozolomide resistance and prognosis of patients with malignant gliomas: a population-based study in China. Cancer Gene Ther, 2017,24(5):215–220
Li K, Lu D, Guo Y, et al. Trends and patterns of incidence of diffuse glioma in adults in the United States, 1973–2014. Cancer Med, 2018,7(10):5281–5290
Ehtesham M, Black KL, Yu JS. Recent Progress in Immunotherapy for Malignant Glioma: Treatment Strategies and Results from Clinical Trials. Cancer Control, 2004,11(3):192–207
Yao J, Caballero OL, Yung WKA, et al. Tumor subtype-specific cancer-testis antigens as potential biomarkers and immunotherapeutic targets for cancers. Cancer Immunol Res, 2014,2(4):371–379
Salmaninejad A, Zamani MR, Pourvahedi M, et al. Cancer/Testis Antigens: Expression, Regulation, Tumor Invasion, and Use in Immunotherapy of Cancers. Immunol Invest, 2016,45(7):619–640
Freitas M, Malheiros S, Stávale JN, et al. Expression of Cancer/Testis Antigens is Correlated with Improved Survival in Glioblastoma. Oncotarget, 2013,4(4):636–646
Shi L, Zhang QM, Wei ZD, et al. Expression Status and Prognostic Value of cancer/testis antigen OY-TES-1 in Glioma. Int J Clin Exp Pathol, 2016,9(2):1598–1607
Li X, Yan J, Fan R, et al. Serum immunoreactivity of cancer/testis antigen OY-TES-1 and its tissues expression in glioma. Oncol Lett, 2017,13(5):3080–3086
He SJ, Gu YY, Yu L, et al. High expression and frequently humoral immune response of melanoma-associated antigen D4 in glioma. Int J Clin Exp Pathol, 2014,7(5):2350–2360
Lee SY, Obata Y, Yoshida M, et al. Immunomic analysis of human sarcoma. Proc Natl Acad Sci U S A, 2003,100(5):2651–2656
Park JH, Song MH, Lee CH, et al. Expression of the human cancer/testis antigen NY-SAR-35 is activated by CpG island hypomethylation. Biotechnol Lett, 2011,33(6):1085–1091
Song MH, Kim YR, Bae JH, et al. A cancer/testis antigen, NY-SAR-35, induces EpCAM, CD44, and CD133, and activates ERK in HEK293 cells. Biochem Biophys Res Commun, 2017,484(2):298–303
Song MH, Kim YR, Lee JW, et al. Cancer/testis antigen NY-SAR-35 enhances cell proliferation, migration, and invasion. Int J Oncol, 2016,48(2):569–576
Song M, Kim Y, Bae J, et al. Effect of cancer/testis antigen NYSAR35 on the proliferation, migration and invasion of cancer cells. Oncol Lett, 2017,13(2):784–790
Komori T. The 2016 WHO Classification of Tumours of the Central Nervous System: The Major Points of Revision. Neurol Med Chir (Tokyo), 2017,57(7):301–311
Zhang QM, He SJ, Shen N, et al. Overexpression of MAGE-D4 in colorectal cancer is a potentially prognostic biomarker and immunotherapy target. Int J Clin Exp Pathol, 2014,7(7):3918–3927
Luo B, Yun X, Fan R, et al. Cancer testis antigen OY-TES-1 expression and serum immunogenicity in colorectal cancer: its relationship to clinicopathological parameters. Int J Clin Exp Pathol, 2013,6(12):2835–2845
Han CP, Lee MY, Tzeng SL, et al. Nuclear Receptor Interaction Protein (NRIP) expression assay using human tissue microarray and immunohistochemistry technology confirming nuclear localization. J Exp Clin Cancer Res, 2008,27(1):1–7
Fu J, Luo B, Guo WW, et al. Down-regulation of cancer/testis antigen OY-TES-1 attenuates malignant behaviors of hepatocellular carcinoma cells in vitro. Int J Clin Exp Pathol, 2015,8(7):7786–7797
Cen YY, Guo WW, Luo B, et al. Knockdown of OY-TES-1 by RNAi causes cell cycle arrest and migration decrease in bone marrow-derived mesenchymal stem cells. Cell Biology International, 2012,36(10):917–922
Fabrício F. Costa, Blanc K L, et al. Concise Review: Cancer/Testis Antigens, Stem Cells, and Cancer. Stem Cells, 2010,25(3):707–711
Ghafouri-Fard S, Modarressi MH. Cancer-testis antigens: potential targets for cancer immunotherapy. Arch Iran Med, 2009,12(4):395–404
Salmaninejad A, Zamani MR, Pourvahedi M, et al. Cancer/Testis Antigens: Expression, Regulation, Tumor Invasion, and Use in Immunotherapy of Cancers. Immunol Invest, 2016,45(7):619–640
Scanlan MJ, Simpson AJG, Old LJ. The cancer/testis genes: Review, standardization, and commentary. Cancer Immun, 2004,4(1):1
Kim YD, Park HR, Song MH, et al. Pattern of cancer/testis antigen expression in lung cancer patients. Int J Mol Med, 2012,29(4):656–662
Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer, 2009,9(3):153–166
Dulic V, Lees E, Reed S. Association of human cyclin E with a periodic G1-S phase protein kinase. Science, 1992,257(5078):1958–1961
Koff A, Giordano A, Desai D, et al. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science, 1992,257(5077):1689–1694
Hinds PW, Mittnacht S, Dulic V, et al. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell, 1992,70(6):993–1006
Hatakeyama M, Brill JA, Fink GR, et al. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev, 1994,8(15):1759–1771
Pines J, Hunter T. Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Nature, 1990,346(6286):760–763
Tsai LH, Harlow E, Meyerson M. Meyerson, Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature, 1991, 353(6340):174–177
Elledge SJ, Richman R, Hall FL, et al. CDK2 encodes a 33-kDa cyclin A-associated protein kinase and is expressed before CDC2 in the cell cycle. Proc Natl Acad Sci USA, 1992,89(7):2907–2911
Cardoso MC, Leonhardt H, Nadal-Ginard B. Reversal of terminal differentiation and control of DNA replication: cyclin A and Cdk2 specifically localize at subnuclear sites of DNA replication. Cell, 1993,74(6):979–992
Heuvel SVD, Harlow E. Distinct roles for Cyclin-dependent kinases in cell cycle control. Science, 1994,262(5142):2050–2054
Ishimi Y, Komamura-Kohno Y, You ZY, et al. Inhibition of Mcm4,6,7 Helicase Activity by Phosphorylation with Cyclin A/Cdk2. J Biol Chem, 2000,275(21):16235–16241
Omar F, Zhengying W, Knudsen KE, et al. Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition. Endocrinology, 2010(3):896–908
Kawana H, Tamaru JI, Tanaka T, et al. Role of p27Kip1 and Cyclin-Dependent Kinase 2 in the Proliferation of Non-Small Cell Lung Cancer. Am J Pathol, 1998,153(2):505–513
Li Y, Zhang J, Gao W, et al. Insights on Structural Characteristics and Ligand Binding Mechanisms of CDK2. Int J Mol Sci, 2015,16(12):9314–9340
Ali S, Heathcote DA, Kroll SHB, et al. The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity. Cancer Res, 2009,69(15):6208–6215
Zou H, Henzel WJ, Liu X, et al. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent. Cell, 1997,90(3):405–413.
Nuez G, Benedict MA, Hu Y, et al. Caspases: the proteases of the apoptotic pathway. Oncogene, 1998,17(25):3237–3245.
Kim B, Srivastava SK, Kim SH. Caspase-9 as a therapeutic target for treating cancer. Expert Opin Ther Targets, 2015,19(1):113–127
Zhou Q, Liao H, Huo Z, et al. Cancer/Testis Antigens Trigger Epithelial-Mesenchymal Transition and Genesis of Cancer Stem-Like Cells. Curr Pharm Des, 2015,21(10):1292–1300
Yao D, Dai C, Peng S. Mechanism of the Mesenchymal-Epithelial Transition and Its Relationship with Metastatic Tumor Formation. 2011,9(12):1608–1620
Park JH, Song MH, Lee CH, et al. Expression of the human cancer/testis antigen NY-SAR-35 is activated by CpG island hypomethylation. Biotechnol Lett, 2011,33(6):1085–1091
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This work was supported by grants from the National Natural Science Foundation of China (No. 81960453, No. 81860445), Natural Science Foundation of Guangxi Province (No. 2022GXNSFAA035639, No. 2018GXNSFAA281050, No. 2018GXNSFAA050151), Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University) and Ministry of Education (No. GK2018-09, No. GKE 2019-08, No. GKE-ZZ202006), and Guangxi First-class Discipline Construction Project in Basic Medical Sciences (No. GXMUBMSTC-T07, No. GXMUBMSTCF-G04).
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Bi, Sq., Peng, Y., Wei, Zd. et al. FMR1NB Involved in Glioma Tumorigenesis Is a Promising Target for Prognosis and Therapy. CURR MED SCI 42, 803–816 (2022). https://doi.org/10.1007/s11596-022-2586-4
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DOI: https://doi.org/10.1007/s11596-022-2586-4