Transmembrane protein 39A (TMEM39A) belongs to the TMEM39 family. TMEM39A gene is a susceptibility locus for multiple sclerosis. In addition, TMEM39A seems to be implicated in systemic lupus erythematosus. However, any possible involvement of TMEM39A in cancer remains largely unknown. In the present report, we provide evidence that TMEM39A may play a role in brain tumors. Western blotting using an anti-TMEM39A antibody indicated that TMEM39A was overexpressed in glioblastoma cell lines, including U87-MG and U251-MG. Deep-sequencing transcriptomic profiling of U87-MG and U251-MG cells revealed that TMEM39A transcripts were upregulated in such cells compared with those of the cerebral cortex. Confocal microscopic analysis of U251-MG cells stained with anti-TMEM39A antibody showed that TMEM39A was located in dot-like structures lying close to the nucleus. TMEM39A probably located to mitochondria or to endosomes. Immunohistochemical analysis of glioma tissue specimens indicated that TMEM39A was markedly upregulated in such samples. Bioinformatic analysis of the Rembrandt knowledge base also supported upregulation of TMEM39A mRNA levels in glioma patients. Together, the results afford strong evidence that TMEM39A is upregulated in glioma cell lines and glioma tissue specimens. Therefore, TMEM39A may serve as a novel diagnostic marker of, and a therapeutic target for, gliomas and other cancers.
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Friedmann-Morvinski, D., Bushong, E.A., Ke, E., Soda, Y., Marumoto, T., Singer, O., Ellisman, M.H. and Verma, I.M. (2012) Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science, 338, 1080–1084.
Arif, S.H., Pandith, A.A., Bhat, A.R., Ramzan, A.U., Malik, N.K., Chibber, S.S., Wani, A.A., Tabasum, R. and Kirmani, A. (2015) EGFR and PTEN gene mutation status in glioblastoma patients and their prognostic impact on patient’s survival. J. Carcinog. Mutagen., 6, 218.
Virk, S.M., Gibson, R.M., Quinones-Mateu, M.E. and Barnholtz-Sloan, J.S. (2015) Identification of variants in primary and recurrent glioblastoma using a cancer-specific gene panel and whole exome sequencing. PLoS ONE, 10, e0124178.
Wesseling, P., Ruiter, D.J. and Burger, P.C. (1997) Angiogenesis in brain tumors; pathobiological and clinical aspects. J Neurooncol., 32, 253–265.
Jain, R.K., di Tomaso, E., Duda, D.G., Loeffler, J.S., Sorensen, A.G. and Batchelor, T.T. (2007) Angiogenesis in brain tumours. Nat. Rev. Neurosci., 8, 610–622.
Das, S. and Marsden, P.A. (2013) Angiogenesis in glioblastoma. N. Engl. J. Med., 369, 1561–1563.
Carmeliet, P. and Jain, R.K. (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature, 473, 298–307.
Norden, A.D., Drappatz, J. and Wen, P.Y. (2008) Novel anti-angiogenic therapies for malignant gliomas. Lancet Neurol., 7, 1152–1160.
Chinot, O.L., Macdonald, D.R., Abrey, L.E., Zahlmann, G., Kerloeguen, Y. and Cloughesy, T.F. (2013) Response assessment criteria for glioblastoma: practical adaptation and implementation in clinical trials of antiangiogenic therapy. Curr. Neurol. Neurosci. Rep., 13, 347.
Chinot, O.L., Wick, W., Mason, W., Henriksson, R., Saran, F., Nishikawa, R., Carpentier, A.F., Hoang-Xuan, K., Kavan, P., Cernea, D., Brandes, A.A., Hilton, M., Abrey, L. and Cloughesy, T. (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med., 370, 709–722.
Gilbert, M.R., Dignam, J.J., Armstrong, T.S., Wefel, J.S., Blumenthal, D.T., Vogelbaum, M.A., Colman, H., Chakravarti, A., Pugh, S., Won, M., Jeraj, R., Brown, P.D., Jaeckle, K.A., Schiff, D., Stieber, V.W., Brachman, D.G., Werner-Wasik, M., Tremont-Lukats, I.W., Sulman, E.P., Aldape, K.D., Curran, W.J., Jr. and Mehta, M.P. (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med., 370, 699–708.
Hao, Y., Colak, R., Teyra, J., orbi-Verge, C., Ignatchenko, A., Hahne, H., Wilhelm, M., Kuster, B., Braun, P., Kaida, D., Kislinger, T. and Kim, P.M. (2015) Semi-supervised learning predicts approximately one third of the alternative splicing isoforms as functional proteins. Cell Rep., 12, 183–189.
Moon, C.P. and Fleming, K.G. (2011) Side-chain hydrophobicity scale derived from transmembrane protein folding into lipid bilayers. Proc. Natl. Acad. Sci. U.S.A., 108, 10174–10177.
International Multiple Sclerosis Genetics Consortium (IMSGC) (2010) Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. Hum. Mol. Genet., 19, 953–962.
Varadé, J., Comabella, M., Ortiz, M.A., Arroyo, R., Fernández, O., Pinto-Medel, M.J., Fedetz, M., Izquierdo, G., Lucas, M., Gómez, C.L., Rabasa, A.C., Alcina, A., Matesanz, F., Alloza, I., Antigüedad, A., García-Barcina, M., Otaegui, D., Olascoaga, J., Saiz, A., Blanco, Y., Montalbán, X., Vandenbroeck, K. and Urcelay, E. (2012) Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of TMEM39A, IL12B and CBLB [correction of CLBL] genes. Mult. Scler., 18, 959–965.
You, Y., Zhai, Z.F., Chen, F.R., Chen, W. and Hao, F. (2015) Autoimmune risk loci of IL12RB2, IKZF1, XKR6, TMEM39A and CSK in Chinese patients with systemic lupus erythematosus. Tissue Antigens, 85, 200–203.
Sheng, Y.J., Xu, J.H., Wu, Y.G., Zuo, X.B., Gao, J.P., Lin, Y., Zhu, Z.W., Wen, L.L., Yang, C., Liu, L., Cheng, Y.Y., Chang, Y., Yang, L.L., Zhou, F.S., Tang, X.F., Zheng, X.D., Yin, X.Y., Tang, H.Y., Sun, L.D., Cui, Y., Yang, S. and Zhang, X.J. (2015) Association analyses confirm five susceptibility loci for systemic lupus erythematosus in the Han Chinese population. Arthritis Res. Ther., 17, 85.
Lessard, C.J., Adrianto, I., Ice, J.A., Wiley, G.B., Kelly, J.A., Glenn, S.B., Adler, A.J., Li, H., Rasmussen, A., Williams, A.H., Ziegler, J., Comeau, M.E., Marion, M., Wakeland, B.E., Liang, C., Ramos, P.S., Grundahl, K.M., Gallant, C.J., Alarcón-Riquelme, M.E., Alarcón, G.S., Anaya, J.M., Bae, S.C., Boackle, S.A., Brown, E.E., Chang, D.M., Cho, S.K., Criswell, L.A., Edberg, J.C., Freedman, B.I., Gilkeson, G.S., Jacob, C.O., James, J.A., Kamen, D.L., Kimberly, R.P., Kim, J.H., Martin, J., Merrill, J.T., Niewold, T.B., Park, S.Y., Petri, M.A., Pons-Estel, B.A., Ramsey-Goldman, R., Reveille, J.D., Scofield, R.H., Song, Y.W., Stevens, A.M., Tsao, B.P., Vila, L.M., Vyse, T.J., Yu, C.Y., Guthridge, J.M., Kaufman, K.M., Harley, J.B., Wakeland, E.K., Langefeld, C.D., Gaffney, P.M., Montgomery, C.G. and Moser, K.L. (2012) Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am. J. Hum. Genet., 90, 648–660.
Kim, A.Y., Kwak, J.H., Je, N.K., Lee, Y.H. and Jung, Y.S. (2015) Epithelial-mesenchymal transition is associated with acquired resistance to 5-fluorocuracil in HT-29 colon cancer cells. Toxicol. Res., 31, 151–156.
Li, Y., Park, J., Piao, L., Kong, G., Kim, Y., Park, K.A., Zhang, T., Hong, J., Hur, G.M., Seok, J.H., Choi, S.W., Yoo, B.C., Hemmings, B.A., Brazil, D.P., Kim, S.H. and Park, J. (2013) PKB-mediated PHF20 phosphorylation on Ser291 is required for p53 function in DNA damage. Cell. Signal., 25, 74–84.
Kim, I.S., Yang, S.Y., Han, J.H., Jung, S.H., Park, H.S. and Myung, C.S. (2015) Differential gene expression in GPR40-overexpressing pancreatic β-cells treated with linoleic acid. Korean J. Physiol. Pharmacol., 19, 141–149.
Bioinformatics, U.G. (2015) Human Genome Sequencing Consortium. Available from: https://doi.org/genome.ucsc.edu/.
Kim, D. and Salzberg, S. (2015) TopHat 2.1.0 release [cited 2015 Jun 29]. Available from: https://doi.org/ccb.jhu.edu/software/tophat/index.shtml/.
Na, C.H., Hong, J.H., Kim, W.S., Shanta, S.R., Bang, J.Y., Park, D., Kim, H.K. and Kim, K.P. (2015) Identification of protein markers specific for papillary renal cell carcinoma using imaging mass spectrometry. Mol. Cells, 38, 624–629.
Cheon, J.M., Kim, D.I. and Kim, K.S. (2015) Insulin sensitivity improvement of fermented Korean Red Ginseng (Panax ginseng) mediated by insulin resistance hallmarks in old-aged ob/ob mice. J. Ginseng Res., 39, 331–337.
Zhang, J., Ma, Y., Qiu, M., Yang, L., Bu, Y. and Tang, X. (2014) Correlation between TMEM39A gene polymorphism and systemic lupus erythematosus in Chinese Han patients. Nan Fang Yi Ke Da Xue Xue Bao, 34, 556–559.
Goodman, S.R. (2008) Medical cell biology in Medical Cell Biology (Goodman, S.R. Ed.). Academic Press, p. 37.
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Park, J., Lee, H., Tran, Q. et al. Recognition of Transmembrane Protein 39A as a Tumor-Specific Marker in Brain Tumor. Toxicol Res. 33, 63–69 (2017). https://doi.org/10.5487/TR.2017.33.1.063