The two most common histological subtypes of malignant germ cell tumour are distinguished by global microRNA profiles, associated with differential transcription factor expression

Abstract

BackgroundWe hypothesised that differences in microRNA expression profiles contribute to the contrasting natural history and clinical outcome of the two most common types of malignant germ cell tumour (GCT), yolk sac tumours (YSTs) and germinomas.ResultsBy direct comparison, using microarray data for paediatric GCT samples and published qRT-PCR data for adult samples, we identified microRNAs significantly up-regulated in YSTs (n = 29 paediatric, 26 adult, 11 overlapping) or germinomas (n = 37 paediatric). By Taqman qRT-PCR we confirmed differential expression of 15 of 16 selected microRNAs and further validated six of these (miR-302b, miR-375, miR-200b, miR-200c, miR-122, miR-205) in an independent sample set. Interestingly, the miR-302 cluster, which is over-expressed in all malignant GCTs, showed further over-expression in YSTs versus germinomas, representing six of the top eight microRNAs over-expressed in paediatric YSTs and seven of the top 11 in adult YSTs. To explain this observation, we used mRNA expression profiles of paediatric and adult malignant GCTs to identify 10 transcription factors (TFs) consistently over-expressed in YSTs versus germinomas, followed by linear regression to confirm associations between TF and miR-302 cluster expression levels. Using the sequence motif analysis environment iMotifs, we identified predicted binding sites for four of the 10 TFs (GATA6, GATA3, TCF7L2 and MAF) in the miR-302 cluster promoter region. Finally, we showed that miR-302 family over-expression in YST is likely to be functionally significant, as mRNAs down-regulated in YSTs were enriched for 3' untranslated region sequences complementary to the common seed of miR-302a~miR-302d. Such mRNAs included mediators of key cancer-associated processes, including tumour suppressor genes, apoptosis regulators and TFs.ConclusionsDifferential microRNA expression is likely to contribute to the relatively aggressive behaviour of YSTs and may enable future improvements in clinical diagnosis and/or treatment.

Recent Advances in Understanding the Etiology and Pathogenesis of Pediatric Germ Cell Tumors

“…For study marked with *there is no distinction of the childhood tumors into histologic subtypes, and DG/SEM/GER and YST are rated collectively. 5,[23][24][25][26][27][28][29]33,37,38,40,[42][43][44][45][46][47][48][49]51,54 DG indicates dysgerminoma; GER, germinoma; IHC, immunohistochemistry; IT, immature teratoma; MT, mature teratoma; SEM, seminoma; SNP, single nucleotide polymorphism; YST, yolk sac tumor.…”

“…42 In contrast, numerous miRNA were significantly higher expressed in YST, including some miRNAs previously identified in this tumor type by global miRNA profiling. 43 When the pediatric GCT data were compared with data from adult GCTs from previous work, the RNA and miRNA profiles differed with age (pediatric vs. adult). Germinomas showed an undifferentiated and pluripotent phenotype, overexpressing the embryonal stem cell markers NANOG, OCT-3/4, and UTF1, whereas YSTs displayed extraembryonic differentiation maintaining a proliferative phenotype.…”

“…44 It opens up for use in future clinical diagnosis and treatment, as the differential miRNA expression (especially miR-302) is likely to contribute to the relatively aggressive behavior of YST. 43 The miR-371-373 is involved in maintaining the pluripotent state, whereas miR-302 is induced during the first stages of in vitro differentiation. The miR-302 levels are high in extraembryonic differentiated tumors like YSTs, whereas virtually undetectable in somatically differentiated teratomas.…”

Altered Profile of Seminal Plasma MicroRNAs in the Molecular Diagnosis of Male Infertility

“…miR-34c controls germ cell differentiation by preferentially downregulating genes that are less expressed in germ cells (16 ). miR-122, a liverspecific miRNA, is also overproduced in all yolk sac tumors (31 ), suggesting its association with reproductive system disorders. In addition, infection, inflammation, and cellular apoptosis of the male reproductive tract are well-known primary etiologic factors of male infertility (32,33 ).…”

Role of microRNAs in mammalian spermatogenesis and testicular germ cell tumors

“…In addition, studies demonstrate that some serum miRNAs could act as biomarkers to detect germ cell tumors. However, future studies Involved in over-ruling cellular senescence Voorhoeve et al (2006Voorhoeve et al ( , 2007 and Gillis et al (2007) miR375 Overexpressed in pediatric YSTs IGR1R Tumor suppressor, inhibits metastasis Murray et al (2010) and Hudson et al (2013) miR142-3p TGCT cell lines Represses PTPN23 expression Tanaka et al (2013) SE, seminomas; NS, non-seminomas; EC, embryonal carcinoma; YST, yolk sack tumors; SS, spermatocytic seminoma; TGCTs, testicular germ cell tumors; GCT, germ cell tumor.…”