Cancer/Testis genes in relation to sperm biology and function

Document Type : Mini Review


1 Clinical Anatomy/ Immunology Division, Department of Medicine, University of Fribourg, Fribourg, Switzerland

2 Medical Genetics Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

3 Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran


Cancer testis antigens (CTAs), a large family of tumor-associated and immunogenic antigens expressed in human tumors of various histological origins, are highly restricted to the testis and trophoblast. CTAs have been identified as potent targets for tumor-specific immunotherapeutic advances and have immensely lead to the development of different clinical trials of CTA-based vaccine therapy because of their resilient in vivo immunogenicity and tumor-restricted expression pattern. Bladder cancer, non-small cell lung carcinoma, and melanoma are grouped as high CT gene expressors. Prostate and breast cancer as moderate, and colon and renal cancers are considered as low CT gene expressors. Large percentages of these identified CT genes are expressed during spermatogenesis but their function is still vaguely unknown. Researchers have taken a keen interest in CT genes as pertaining to their role in tumor growth and spermatogenesis. Testis has many similarities with cancerous tissues like cell division, immigration, and immortalization. The aim is to give a concise in-depth review on the role of some specific CT genes in spermatogenesis. 


1. Scanlan MJ, Simpson AJ, Old LJ. The cancer/testis genes: review, standardization, and commentary. Cancer Immun 2004; 4:1-15.
2. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 2005; 5:615-625.
3. Nourashrafeddin S, Dianatpour M, Aarabi M, Mobasheri MB, Kazemi-Oula G, Modarressi MH. Elevated Expression of the Testis-specific Gene WBP2NL in Breast Cancer. Biomark Cancer 2015; 7:19-24.
4. Mobasheri MB, Shirkoohi R, Modarressi MH. Cancer/testis OIP5 and TAF7L genes are Up-regulated in breast cancer. Asian Pac J Cancer Prev 2015; 16:4623-4628.
5. Mobasheri MB, Shirkoohi R, Zendehdel K, Jahanzad I, Talebi S, Afsharpad M, Modarressi MH. Transcriptome analysis of the cancer/testis genes, DAZ1, AURKC, and TEX101, in breast tumors and six breast cancer cell lines. Tumour Biol 2015; 36:8201-8206.
6. Jungbluth AA, Stockert E, Chen YT, Kolb D, Iversen K, Coplan K, et al.  Monoclonal antibody MA454 reveals a heterogeneous expression pattern of MAGE-1 antigen in formalin-fixed paraffin embedded lung tumours. Br J Cancer 2000; 83:493-497.
7. Mobasheri MB, Modarressi MH, Shabani M, Asgarian H, Sharifian RA, Vossough P, Shokri F. Expression of the testis-specific gene, TSGA10, in Iranian patients with acute lymphoblastic leukemia (ALL). Leuk Res 2006; 30:883-889.
8. Scanlan MJ, Gordon CM, Williamson B, Lee SY, Chen YT, Stockert E, et al. Identification of cancer/testis genes by database mining and mRNA expression analysis. Int J Cancer 2002; 98:485-492.
9. Zendman AJ, Ruiter DJ, Van Muijen GN. Cancer/testis-associated genes: identification, expression profile, and putative function. J Cell Physiol 2003; 194:272-288.
10. Costa FF, Le Blanc K, Brodin B. Concise review: cancer/testis antigens, stem cells, and cancer. Stem Cells 2007; 25:707-711.
11. Kalejs M, Erenpreisa J. Cancer/testis antigens and gametogenesis: a review and "brain-storming" session. Cancer Cell Int 2005; 5:4.
12. Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, et al. The DNA sequence of the human X chromosome. Nature 2005; 434:325-337.
13. Hofmann O, Caballero OL, Stevenson BJ, Chen YT, Cohen T, Chua R, et al. Genome-wide analysis of cancer/testis gene expression. Proc Natl Acad Sci U S A 2008; 105:20422-20427.
14. Doyle JM, Gao J, Wang J, Yang M, Potts PR. MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell 2010; 39:963-974.
15. Cheng YH, Wong EW, Cheng CY. Cancer/testis (CT) antigens, carcinogenesis and spermatogenesis. Spermato-genesis 2011; 1:209-220.
16. Dalerba P, Frascella E, Macino B, Mandruzzato S, Zambon A, Rosolen A, et al. MAGE, BAGE and GAGE gene expression in human rhabdomyosarcomas. Int J Cancer 2001; 93:85-90.
17. von Boehmer L, Keller L, Mortezavi A, Provenzano M, Sais G, Hermanns T, et al. MAGE-C2/CT10 protein expression is an independent predictor of recurrence in prostate cancer. PLoS One 2011; 6:e21366.
18. Gjerstorff MF, Kock K, Nielsen O, Ditzel HJ. MAGE-A1, GAGE and NY-ESO-1 cancer/testis antigen expression during human gonadal development. Hum Reprod 2007; 22:953-960.
19. Takebe M, Onohara Y, Yokota S. Expression of MAEL in nuage and non-nuage compartments of rat spermatogenic cells and colocalization with DDX4, DDX25 and MIWI. Histochem Cell Biol 2013; 140:169-181.
20. Vasileva A, Tiedau D, Firooznia A, Muller-Reichert T, Jessberger R. Tdrd6 is required for spermiogenesis, chromatoid body architecture, and regulation of miRNA expression. Curr Biol 2009; 19:630-639.
21. Fratta E, Coral S, Covre A, Parisi G, Colizzi F, Danielli R, Nicolay HJ, Sigalotti L, Maio M. The biology of cancer testis antigens: putative function, regulation and therapeutic potential. Mol Oncol 2011; 5:164-182.
22. Mirandola L, M JC, Cobos E, Bernardini G, Jenkins MR, Kast WM, Chiriva-Internati M. Cancer testis antigens: novel biomarkers and targetable proteins for ovarian cancer. Int Rev Immunol 2011; 30:127-137.
23. Shen Y, Xu J, Yang X, Liu Y, Ma Y, Yang D, et al. Evidence for the involvement of the proximal copy of the MAGEA9 gene in Xq28-linked CNV67 specific to spermatogenic failuredagger. Biol Reprod 2017; 96:610-616.
24. Meuwissen RL, Offenberg HH, Dietrich AJ, Riesewijk A, van Iersel M, Heyting C. A coiled-coil related protein specific for synapsed regions of meiotic prophase chromosomes. EMBO J 1992; 11:5091-5100.
25. Kuramochi-Miyagawa S, Kimura T, Ijiri TW, Isobe T, Asada N, Fujita Y, et al. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development 2004; 131:839-849.
26. Lim AK, Knowles BB. Controlling endogenous retroviruses and their chimeric transcripts during natural reprogramming in the Oocyte. J Infect Dis 2015; 212:S47-51.
27. Reuter M, Chuma S, Tanaka T, Franz T, Stark A, Pillai RS. Loss of the Mili-interacting Tudor domain-containing protein-1 activates transposons and alters the Mili-associated small RNA profile. Nat Struct Mol Biol 2009; 16:639-646.
28. Fereydouni B, Salinas-Riester G, Heistermann M, Dressel R, Lewerich L, Drummer C, et al. Long-term oocyte-like cell development in cultures derived from neonatal marmoset monkey ovary. Stem Cells Int 2016; 2016:2480298.
29. Soper SF, van der Heijden GW, Hardiman TC, Goodheart M, Martin SL, de Boer P, et al.  Mouse maelstrom, a component of nuage, is essential for spermatogenesis and transposon repression in meiosis. Dev Cell 2008; 15:285-297.
30. Ikawa M, Tokuhiro K, Yamaguchi R, Benham AM, Tamura T, Wada I, et al.  Calsperin is a testis-specific chaperone required for sperm fertility. J Biol Chem 2011; 286:5639-5646.
31. Jackman SM, Kong X, Fant ME. Plac1 (placenta-specific 1) is essential for normal placental and embryonic development. Mol Reprod Dev 2012; 79:564-572.
32. Miki K, Willis WD, Brown PR, Goulding EH, Fulcher KD, Eddy EM. Targeted disruption of the Akap4 gene causes defects in sperm flagellum and motility. Dev Biol 2002; 248:331-342.
33. Fiedler SE, Dudiki T, Vijayaraghavan S, Carr DW. Loss of R2D2 proteins ROPN1 and ROPN1L causes defects in murine sperm motility, phosphorylation, and fibrous sheath integrity. Biol Reprod 2013; 88:41.
34. Fiedler SE, Sisson JH, Wyatt TA, Pavlik JA, Gambling TM, Carson JL, Carr DW. Loss of ASP but not ROPN1 reduces mammalian ciliary motility. Cytoskeleton (Hoboken) 2012; 69:22-32.
35. Han C, Kwon JT, Park I, Lee B, Jin S, Choi H, et al. Impaired sperm aggregation in Adam2 and Adam3 null mice. Fertil Steril 2010; 93:2754-2756.
36. Kohn MJ, Sztein J, Yagi R, DePamphilis ML, Kaneko KJ. The acrosomal protein Dickkopf-like 1 (DKKL1) facilitates sperm penetration of the zona pellucida. Fertil Steril 2010; 93:1533-1537.
37. de Vries FA, de Boer E, van den Bosch M, Baarends WM, Ooms M, Yuan L, et al. Mouse Sycp1 functions in synaptonemal complex assembly, meiotic recombination, and XY body formation. Genes Dev 2005; 19:1376-1389.
38. Yang F, Eckardt S, Leu NA, McLaughlin KJ, Wang PJ. Mouse TEX15 is essential for DNA double-strand break repair and chromosomal synapsis during male meiosis. J Cell Biol 2008; 180:673-679.
39.  Bolcun-Filas E, Hall E, Speed R, Taggart M, Grey C, de Massy B, et al. Mutation of the mouse Syce1 gene disrupts synapsis and suggests a link between synaptonemal complex structural components and DNA repair. PLoS Genet 2009; 5:e1000393.
40. Romanienko PJ, Camerini-Otero RD. The mouse Spo11 gene is required for meiotic chromosome synapsis. Mol Cell 2000; 6:975-987.
41. Shin YH, Choi Y, Erdin SU, Yatsenko SA, Kloc M, Yang F, et al. Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in mammalian meiosis. PLoS Genet 2010; 6:e1001190.
42. Suzuki T, Kosaka-Suzuki N, Pack S, Shin DM, Yoon J, Abdullaev Z, et al.  Expression of a testis-specific form of Gal3st1 (CST), a gene essential for spermatogenesis, is regulated by the CTCF paralogous gene BORIS. Mol Cell Biol 2010; 30:2473-2484.
43. Shang E, Nickerson HD, Wen D, Wang X, Wolgemuth DJ. The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation. Development 2007; 134:3507-3515.
44. Pan J, Goodheart M, Chuma S, Nakatsuji N, Page DC, Wang PJ. RNF17, a component of the mammalian germ cell nuage, is essential for spermiogenesis. Development 2005; 132:4029-4039.
45. Kitamura K, Yanazawa M, Sugiyama N, Miura H, Iizuka-Kogo A, Kusaka M, et al.  Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 2002; 32:359-369.
46. Chen TR, Wang P, Carroll LK, Zhang YJ, Han BX, Wang F. Generation and characterization of Tmeff2 mutant mice. Biochem Biophys Res Commun 2012; 425:189-194.
47. Pan J, Eckardt S, Leu NA, Buffone MG, Zhou J, Gerton GL, et al. Inactivation of Nxf2 causes defects in male meiosis and age-dependent depletion of spermatogonia. Dev Biol 2009; 330:167-174.
48. Odet F, Duan C, Willis WD, Goulding EH, Kung A, Eddy EM, Goldberg E. Expression of the gene for mouse lactate dehydrogenase C (Ldhc) is required for male fertility. Biol Reprod 2008; 79:26-34.
49. Salmon NA, Reijo Pera RA, Xu EY. A gene trap knockout of the abundant sperm tail protein, outer dense fiber 2, results in preimplantation lethality. Genesis 2006; 44:515-522.
50. Cheng Y, Buffone MG, Kouadio M, Goodheart M, Page DC, Gerton GL, et al. Abnormal sperm in mice lacking the Taf7l gene. Mol Cell Biol 2007; 27:2582-2589.
51. Ono T, Kurashige T, Harada N, Noguchi Y, Saika T, Niikawa N, et al. Identification of proacrosin binding protein sp32 precursor as a human cancer/testis antigen. Proc Natl Acad Sci U S A 2001; 98:3282-3287.
52. Kanemori Y, Koga Y, Sudo M, Kang W, Kashiwabara S, Ikawa M, et al. Biogenesis of sperm acrosome is regulated by pre-mRNA alternative splicing of Acrbp in the mouse. Proc Natl Acad Sci U S A 2016; 113:E3696-3705.
53. Katahira J, Yoneda Y. Nucleocytoplasmic transport of microRNAs and related small RNAs. Traffic 2011; 12:1468-1474.
54. Thomson T, Lin H. The biogenesis and function of PIWI proteins and piRNAs: progress and prospect. Annu Rev Cell Dev Biol 2009; 25:355-376.
55. Saito K, Nishida KM, Mori T, Kawamura Y, Miyoshi K, Nagami T, et al. Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. Genes Dev 2006; 20:2214-2222.
56. Deng W, Lin H. miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Dev Cell 2002; 2:819-830.
57. Lee JH, Schutte D, Wulf G, Fuzesi L, Radzun HJ, Schweyer S,  et al. Stem-cell protein Piwil2 is widely expressed in tumors and inhibits apoptosis through activation of Stat3/Bcl-XL pathway. Hum Mol Genet 2006; 15:201-211.
58. Unhavaithaya Y, Hao Y, Beyret E, Yin H, Kuramochi-Miyagawa S, Nakano T, et al. MILI, a PIWI-interacting RNA-binding protein, is required for germ line stem cell self-renewal and appears to positively regulate translation. J Biol Chem 2009; 284:6507-6519.
59. Aravin A, Gaidatzis D, Pfeffer S, Lagos-Quintana M, Landgraf P, Iovino N, et al.  A novel class of small RNAs bind to MILI protein in mouse testes. Nature 2006; 442:203-207.
60. Heyn H, Ferreira HJ, Bassas L, Bonache S, Sayols S, Sandoval J, et al.  Epigenetic disruption of the PIWI pathway in human spermatogenic disorders. PLoS One 2012; 7:e47892.
61. Huttemann M, Jaradat S, Grossman LI. Cytochrome c oxidase of mammals contains a testes-specific isoform of subunit VIb--the counterpart to testes-specific cytochrome c? Mol Reprod Dev 2003; 66:8-16.
62. Suzuki-Toyota F, Ito C, Toyama Y, Maekawa M, Yao R, Noda T, et al. Factors maintaining normal sperm tail structure during epididymal maturation studied in Gopc-/- mice. Biol Reprod 2007; 77:71-82.
63. Goldberg E, Eddy EM, Duan C, Odet F. LDHC: the ultimate testis-specific gene. J Androl 2010; 31:86-94.
64. Odet F, Gabel SA, Williams J, London RE, Goldberg E, Eddy EM. Lactate dehydrogenase C and energy metabolism in mouse sperm. Biol Reprod 2011; 85:556-564.
65. Aravin AA, Sachidanandam R, Girard A, Fejes-Toth K, Hannon GJ. Developmentally regulated piRNA clusters implicate MILI in transposon control. Science 2007; 316:744-747.
66. Meikar O, Da Ros M, Korhonen H, Kotaja N. Chromatoid body and small RNAs in male germ cells. Reproduction 2011; 142:195-209.
67. Wang J, Saxe JP, Tanaka T, Chuma S, Lin H. Mili interacts with tudor domain-containing protein 1 in regulating spermatogenesis. Curr Biol 2009; 19:640-644.
68. Modarressi MH, Behnam B, Cheng M, Taylor KE, Wolfe J, van der Hoorn FA. Tsga10 encodes a 65-kilodalton protein that is processed to the 27-kilodalton fibrous sheath protein. Biol Reprod 2004; 70:608-615.
69. Chiriva-Internati M, Cobos E, Da Silva DM, Kast WM. Sperm fibrous sheath proteins: a potential new class of target antigens for use in human therapeutic cancer vaccines. Cancer Immun 2008; 8:8.
70. Fiedler SE, Bajpai M, Carr DW. Identification and characterization of RHOA-interacting proteins in bovine spermatozoa. Biol Reprod 2008; 78:184-192.
71.  Miryounesi M, Nayernia K, Mobasheri MB, Dianatpour M, Oko R, Savad S, et al. Evaluation of in vitro spermatogenesis system effectiveness to study genes behavior: monitoring the expression of the testis specific 10 (Tsga10) gene as a model. Arch Iran Med 2014 ;17:692-7.
72. Dianatpour M, Mehdipour P, Nayernia K, Mobasheri MB, Ghafouri-Fard S, Savad S, et al. Expression of Testis Specific Genes TSGA10, TEX101 and ODF3 in Breast Cancer. Iran Red Crescent Med J 2012; 14:722-726.
73. Salehipour P, Nematzadeh M, Mobasheri MB, Afsharpad M, Mansouri K, Modarressi MH. Identification of new TSGA10 transcript variants in human testis with conserved regulatory RNA elements in 5'untranslated region and distinct expression in breast cancer. Biochim Biophys Acta. 2017; 9:973-982.
74. Rahmani Rad F, Mobasheri M, Modarressi MH. TSGA10, as a Cancer/Testis gene. Tehran Univ Med J TUMS Pub 2015; 73:231-242.