Korkola JE, Houldsworth J, Chadalavada RS, Olshen AB, Dobrzynski D, Reuter VE et al.. Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Res 66: 820-827
Adult male germ cell tumors (GCTs) comprise distinct groups: seminomas and nonseminomas, which include pluripotent embryonal carcinomas as well as other histologic subtypes exhibiting various stages of differentiation. Almost all GCTs show 12p gain, but the target genes have not been clearly defined. To identify 12p target genes, we examined Affymetrix (Santa Clara, CA) U133A+B microarray ( approximately 83% coverage of 12p genes) expression profiles of 17 seminomas, 84 nonseminoma GCTs, and 5 normal testis samples. Seventy-three genes on 12p were significantly overexpressed, including GLUT3 and REA (overexpressed in all GCTs) and CCND2 and FLJ22028 (overexpressed in all GCTs, except choriocarcinomas). We characterized a 200-kb gene cluster at 12p13.31 that exhibited coordinated overexpression in embryonal carcinomas and seminomas, which included the known stem cell genes NANOG, STELLA, and GDF3 and two previously uncharacterized genes. A search for other coordinately regulated genomic clusters of stem cell genes did not reveal any genomic regions similar to that at 12p13.31. Comparison of embryonal carcinoma with seminomas revealed relative overexpression of several stem cell-associated genes in embryonal carcinoma, including several core "stemness" genes (EBAF, TDGF1, and SOX2) and several downstream targets of WNT, NODAL, and FGF signaling (FGF4, NODAL, and ZFP42). Our results indicate that 12p gain is a functionally relevant change leading to activation of proliferation and reestablishment/maintenance of stem cell function through activation of key stem cell genes. Furthermore, the differential expression of core stem cell genes may explain the differences in pluripotency between embryonal carcinomas and seminomas.
"A gene centric analysis with graphical representation of the microarray data was exported from Oncomine TM (Compendia Bioscience, Ann Arbor, MI, USA). The following datasets were used: Korkola Seminoma (Korkola et al., 2006), Hendrix Ovarian (Hendrix et al., 2006), Bittner Ovarian (GSE2109) and Giordano adrenal (Giordano et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: The biological function of the inhibin-α subunit in gonadal tumorigenesis is different in human compared to mouse. The inhibin-α subunit is up-regulated in most human ovarian and testicular cancers but knock-out studies in mice showed the inhibin-α subunit is a tumour suppressor with gonadal and adrenal specificity. The inhibin-α subunit is a component of the inhibin/activin signalling pathway which includes activin receptors ActRIIA/IIB and intracellular Smads-2/3. To resolve the incongruity in function in human versus mouse, we re-evaluated the inhibin/activin pathway in human gonadal and adrenal cancers using contemporary protein and mRNA expression data for multiple pathway components rather than inhibin-α alone. We used an inhibin-α antibody raised against the N-terminal domain to compare immunoreactivity with the more commonly used antibody raised against the C-terminal domain. This study also described, for the first time, a comprehensive protein expression profile of activin-βC in reproductive and adrenal cancers, and its effect on a human granulosa cell line, providing evidence for a role in ovarian, testis and adrenal tumour biology. Our data show reduced inhibin-α expression at both protein and mRNA levels, and increased activin signalling in human testicular, ovarian and malignant versus benign forms of adrenal cancer. We also found that activin-C acts as an activin-A antagonist by binding to activin receptor subunits IIA and IIB and modulating the canonical Smad pathway. In conclusion, analysis of the inhibin/activin signalling pathway helps to explain discrepancies arising from studies of only one hormone or subunit and suggests that altered expression of the inhibin and activin subunits is associated with reproductive and adrenal cancer biology.
Molecular Human Reproduction 09/2014; 20(12). DOI:10.1093/molehr/gau074 · 3.75 Impact Factor
"Within individual histological subtypes, however, tumours shared similar protein-coding transcriptomes, regardless of whether they were gonadal or extragonadal in origin (Palmer et al., 2008). As seen for adult seminomas (Korkola et al., 2006), paediatric seminomas were enriched for genes associated with pluripotency and the undifferentiated state [e.g. NANOG, POU5F1 (OCT3/4), TFAP2C and UTF] and paediatric YSTs were associated with genes such as AFP, those involved in differentiation (KRT8, KRT19), lipid metabolism (APOA1, APOA2) and proliferation pathways (Palmer et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Genomic and protein-coding transcriptomic data have suggested that germ cell tumours (GCTs) of childhood are biologically distinct from those of adulthood. Global messenger RNA profiles segregate malignant GCTs primarily by histology, but then also by age, with numerous transcripts showing age-related differential expression. Such differences are likely to account for the heterogeneous clinico-pathological behaviour of paediatric and adult malignant GCTs. In contrast, as global microRNA signatures of human tumours reflect their developmental lineage, we hypothesized that microRNA profiles would identify common biological abnormalities in all malignant GCTs owing to their presumed shared origin from primordial germ cells. MicroRNAs are short, non-protein-coding RNAs that regulate gene expression via translational repression and/or mRNA degradation. We showed that all malignant GCTs over-express the miR-371–373 and miR-302/367 clusters, regardless of patient age, histological subtype or anatomical tumour site. Furthermore, bioinformatic approaches and subsequent Gene Ontology analysis revealed that these two over-expressed microRNAs clusters co-ordinately down-regulated genes involved in biologically significant pathways in malignant GCTs. The translational potential of this finding has been demonstrated with the detection of elevated serum levels of miR-371–373 and miR-302/367 microRNAs at the time of malignant GCT diagnosis, with levels falling after treatment. The tumour-suppressor let-7 microRNA family has also been shown to be universally down-regulated in malignant GCTs, because of abundant expression of the regulatory gene LIN28. Low let-7 levels resulted in up-regulation of oncogenes including MYCN, AURKB and LIN28 itself, the latter through a direct feedback mechanism. Targeting LIN28, or restoring let-7 levels, both led to effective inhibition of this pathway. In summary, paediatric malignant GCTs show biological differences from their adult counterparts at a genomic and protein-coding transcriptome level, whereas they both display very similar microRNA expression profiles. These similarities and differences may be exploited for diagnostic and/or therapeutic purposes.
"Computational analysis predicts RHOXF2 to be a testicular cancer candidate gene
 and, in fact, the transcript was detected in several types of human testicular cancers
. Furthermore, in the present study, we show that RHOXF2 overexpression conferred resistance to cisplatin (Figure
3a) and that RHOXF2 is found in several other cancer cell lines, the non-small cell lung carcinoma NCI-H1299, the blast phase chronic myelogenous leukemia K562, the multiple myeloma U266B1, the thyroid gland medullary carcinoma TT (CRL-1803) and the chondrosarcoma SW1353 (Figure
4c; Additional file
[Show abstract][Hide abstract] ABSTRACT: Target identification is a critical step in the lengthy and expensive process of drug development. Here, we describe a genome-wide screening platform that uses systematic overexpression of pooled human ORFs to understand drug mode-of-action and resistance mechanisms. We first calibrated our screen with the well-characterized drug methotrexate. We then identified new genes involved in the bioactivity of diverse drugs including antineoplastic agents and biologically active molecules. Finally, we focused on the transcription factor RHOXF2 whose overexpression conferred resistance to DNA damaging agents. This approach represents an orthogonal method for functional screening and, to our knowledge, has never been reported before.
Genome Medicine 04/2014; 6(4):32. DOI:10.1186/gm549 · 5.34 Impact Factor
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