The Sox genes define a family of transcription factors that play a key role in the determination of cell fate during development. The preferential expression of the Sox15 in the myogenic precursor cells led us to suggest that the Sox15 is involved in the specification of myogenic cell lineages or in the regulation of the fusion of myoblasts to form myotubes during the development and regeneration of skeletal muscle. To identify the physiological function of Sox15 in mice, we disrupted the Sox15 by homologous recombination in mice. Sox15-deficient mice were born at expected ratios, were healthy and fertile, and displayed normal long-term survival rates. Histological analysis revealed the normal ultrastructure of myofibers and the presence of comparable amounts of satellite cells in the skeletal muscles of Sox15
VSIG1, a cell adhesion protein of the immunoglobulin superfamily, is preferentially expressed in stomach, testis, and certain gastric, esophageal and ovarian cancers. Here, we describe the expression patterns of three alternatively spliced isoforms of mouse Vsig1 during pre- and postnatal development of stomach and potential function of Vsig1 in differentiation of gastric epithelia. We show that isoforms Vsig1A and Vsig1B, which differ in the 3′untranslated region, are expressed in the early stages of stomach development. Immunohistochemical analysis revealed that VSIG1 is restricted to the adherens junction of the glandular epithelium. The shorter transcript Vsig1C is restricted to the testis, encodes an N-terminal truncated protein and is presumably regulated by an internal promoter, which is located upstream of exon 1b. To determine whether the 5′ flanking region of exon 1a specifically targets the expression of Vsig1 to stomach epithelia, we generated and analyzed transgenic mice. The 4.8-kb fragment located upstream of exon 1a was sufficient to direct the expression of the reporter gene to the glandular epithelia of transgenic stomach. To determine the role of VSIG1 during the development of stomach epithelia, an X-linked Vsig1 was inactivated in embryonic stem cells (ESCs). Although Vsig1−/Y ESCs were only able to generate low coat color chimeric mice, no male chimeras transmitted the targeted allele to their progeny suggesting that the high contribution of Vsig1−/Y cells leads to the lethality of chimeric embryos. Analysis of chimeric stomachs revealed the differentiation of VSIG1-null cells into squamous epithelia inside the glandular region. These results suggest that VSIG1 is required for the establishment of glandular versus squamous epithelia in the stomach.
To determine the role of BRAF mutation and MAPK signaling as well as the effects of BRAF and MEK directed therapy in gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN), with a focus on highly aggressive gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Using Sanger sequencing of BRAF exon 15 we determined the frequency of BRAF mutations in 71 primary GEP-NENs. MEK phosphorylation was examined by immunohistochemistry in corresponding tissue samples. To evaluate the biological relevance of BRAF mutation and MAPK signaling in GEP-NECs, effects of a pharmacological BRAF and MEK inhibition were analyzed in NEC cell lines both in vitro and in vivo. BRAF mutation was detected in 9.9% of all GEP-NENs. Interestingly, only NECs of the colon harbored BRAF mutations, leading to a mutation frequency of 46.7% in this subgroup of patients. In addition, a BRAF mutation was significantly associated with high levels of MEK phosphorylation (pMEK) and advanced tumor stages. Pharmacological inhibition of BRAF and MEK abrogated NEC cell growth, inducing G1 cell cycle arrest and apoptosis only in BRAF mutated cells. BRAF inhibitor dabrafenib and MEK inhibitor trametinib prevented growth of BRAF positive NEC xenografts. High frequencies of BRAF mutation and elevated expression levels of pMEK were detected in biologically aggressive and highly proliferative colorectal NECs. We provide evidence that targeting BRAF oncogene may represent a therapeutic strategy for patients with BRAF mutant colorectal NECs.
4 DISKUSSION 4.1 Der Magen 4.2 Die Rolle von Foxq1 bei der Magensäuresekretion 4.3 Funktion von Foxq1 in der Embryonal-und Haarentwicklung 4.4 Charakterisierung neuer magenexprimierter Gene 4.4.1 Gastrokine 2 4.4.2 Admp 4.4.3 SA11 4.5 Ausblick
Prostate cancer (PCa) is the most prevailing cancer in the male population and the second-leading cause of cancer-related death in the Western world. Although genomic alterations during PCa development have been recently characterized [1], substantial evidence shows that genome-wide epigenetic insults complement or even precede genetic alterations [2]. Promoter CpG island methylation frequently correlates with gene silencing of functional genes. Therefore we hypothesized that scanning for early-silenced genes by profiling hypermethylation sites of promoter CpG islands would facilitate identification of novel methylation biomarkers with potential functions during prostate carcinogenesis. DNA from 9 primary pT2a tumors and matched normal tissue was subjected to enrichment of methylated sequences using Methyl CpG Immunoprecipitation (MCIp) [3], followed by array co-hybridization using Agilent CpG island arrays. Candidate genes were selected according to 1) hypermethylation in gene promoter regions in tumor tissue and 2) reduced expression in PCa in comparison to normal prostate tissue based on published gene expression datasets. DNA methylation was quantified by mass spectrometry-based EpiTYPER technology [4]. We identified 245 promoter CpG islands corresponding to 207 genes that were hypermethylated in at least 6/9 early stage PCa. Gene ontology enrichment analyses indicated enrichment of homeobox genes, and of gene functions such as regulation of transcription, cellular biosynthesis and morphogenesis, and neuron development. Quantitative methylation analysis of 9 selected candidate genes confirmed significant hypermethylation in the range of 20 -50% in 6/9 tumors of the initial discovery set in comparison with normal prostate tissue. Further validation in 37 sample triplets of matched normal tissue - prostate intraepithelial neoplasia (PIN) - tumor tissue indicated significant hypermethylation of SPG20 (spastic paraplegia 20, p=0.023, Wilcoxon signed-rank test), SPATA6 (spermatogenesis associated 6, p=0.017), and DUOXA1 (dual oxidase maturation factor 1 alpha, p=0.017) already at the PIN stage. Moreover, methylation analysis of 60 prostate tumor samples with increasing malignancy revealed a significant correlation between DNA hypermethylation patterns and biochemical recurrence of prostate cancer (p=0.008, log-rank test). From this genome-wide study we identified relevant biomarkers for early-detection and prognosis of early stage prostate cancer. The identified genes might represent interesting candidates to further investigate their function in the molecular pathogenesis and development of prostate cancer. Citation Format: Po-Hsien J. Huang, Wolfgang Göring, Thomas Hielscher, Dieter Weichenhan, Wolfgang A. Schulz, Christoph Plass, Clarissa Gerhäuser. Genome-wide DNA methylation profiling identifies novel diagnostic and prognostic biomarkers in early stage prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2. doi:10.1158/1538-7445.AM2013-2
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