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See detailNew Target Genes of MITF-Induced microRNA-211 Contribute to Melanoma Cell Invasion
Margue, Christiane UL; Philippidou, Demetra UL; Reinsbach, Susanne UL et al

in PLoS ONE (2013), 8(9),

The non-coding microRNAs (miRNA) have tissue- and disease-specific expression patterns. They down-regulate target mRNAs, which likely impacts on most fundamental cellular processes. Differential ... [more ▼]

The non-coding microRNAs (miRNA) have tissue- and disease-specific expression patterns. They down-regulate target mRNAs, which likely impacts on most fundamental cellular processes. Differential expression patterns of miRNAs are currently being exploited for identification of biomarkers for early disease diagnosis, prediction of progression for melanoma and other cancers and as promising drug targets, since they can easily be inhibited or replaced in a given cellular context. Before successfully manipulating miRNAs in clinical settings, their precise expression levels, endogenous functions and thus their target genes have to be determined. MiR-211, a melanocyte lineage-specific small non-coding miRNA, is located in an intron of TRPM1, a target gene of the microphtalmia-associated transcription factor (MITF). By transcriptionally up-regulating TRPM1, MITF, which is critical for both melanocyte differentiation and survival and for melanoma progression, indirectly drives the expression of miR-211. Expression of this miRNA is often reduced in melanoma samples. Here, we investigated functional roles of miR-211 by identifying and studying new target genes. We show that MITF-correlated miR-211 expression levels are mostly but not always reduced in a panel of 11 melanoma cell lines and in primary and metastatic melanoma compared to normal melanocytes and nevi, respectively. MiR-211 itself only marginally impacted on cell invasion and migration, while perturbation of some new miR-211 target genes, such as AP1S2, SOX11, IGFBP5, and SERINC3 significantly increased invasion. These results and the variable expression levels of miR-211 raise serious doubts on the value of miR-211 as a melanoma tumor-suppressing miRNA and/or as a biomarker for melanoma. [less ▲]

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See detailRegulation of microRNA Expression by STAT1 Transcription Factors - Relevance for Melanoma Development
Schmitt, Martina UL

Doctoral thesis (2013)

The type-II-cytokine IFN-γ (interferon gamma) is not only a pivotal player in innate immune responses but also assumes functions in controlling tumor cell growth by orchestrating cellular responses ... [more ▼]

The type-II-cytokine IFN-γ (interferon gamma) is not only a pivotal player in innate immune responses but also assumes functions in controlling tumor cell growth by orchestrating cellular responses against neoplastic cells. It predominantly triggers cellular responses through the Janus Kinase (Jak)/ Signal Transducer and Activator of Transcription 1 (STAT1) pathway leading to STAT1 binding to the promoter region of target genes. As key regulators of mRNA and protein expression levels, microRNAs (small non-coding RNAs) take part in fine-tuning complex biological processes such as cell proliferation, neoplastic transformation, apoptosis, immune surveillance and differentiation. MiR-29, one of the most interesting miRNA families in humans to date, consists of three mature members miR-29a, miR-29b and miR-29c, which are encoded in two genetic clusters. In this PhD thesis, the miR-29 primary cluster pri-29a~b-1 was shown to be IFN-γ-induced and STAT1-dependently up-regulated in melanoma cell lines. Furthermore, expression levels of mature miR-29a and miR-29b were elevated in cell lines and in primary melanoma patient samples while the pri-29b-2~c cluster was almost undetectable in cell lines. Moreover, tumor-suppressing properties of miR-29 family members have been detected: inhibition of melanoma cell proliferation could be induced by miR-29a, which down-regulated CDK6 (cyclin-dependent kinase 6), an important player in cell cycle G1/S transition. Also, knockdown of CDK6 resulted in reduced proliferation of melanoma cells, suggesting that miR-29-mediated growth inhibitory effects may be brought about by CDK6-downregulation. These findings identify the pri-29a~b-1 cluster as a novel IFN-γ-regulated gene. Furthermore, a potential novel signaling pathway was identified: IFN-γ  Jaks  P-STAT1  miR-29  CDK6, which opens up new connections between miRNAs, interferon signaling and malignant melanoma, possibly clearing the way to novel concepts for new treatment options in the future. [less ▲]

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See detailSignatures of MicroRNAs and selected MicroRNA target genes in human melanoma
Philippidou, Demetra UL; Schmitt, Martina UL; Moser, Dirk et al

in Cancer Research (2010), 70(10), 4163-4173

Small noncoding microRNAs (miRNA) regulate the expression of target mRNAs by repressing their translation or orchestrating their sequence-specific degradation. In this study, we investigated miRNA and ... [more ▼]

Small noncoding microRNAs (miRNA) regulate the expression of target mRNAs by repressing their translation or orchestrating their sequence-specific degradation. In this study, we investigated miRNA and miRNA target gene expression patterns in melanoma to identify candidate biomarkers for early and progressive disease. Because data presently available on miRNA expression in melanoma are inconsistent thus far, we applied several different miRNA detection and profiling techniques on a panel of 10 cell lines and 20 patient samples representing nevi and primary or metastatic melanoma. Expression of selected miRNAs was inconsistent when comparing cell line-derived and patient-derived data. Moreover, as expected, some discrepancies were also detected when miRNA microarray data were correlated with qPCR-measured expression levels. Nevertheless, we identified miRNA-200c to be consistently downregulated in melanocytes, melanoma cell lines, and patient samples, whereas miRNA-205 and miRNA-23b were markedly reduced only in patient samples. In contrast, miR-146a and miR-155 were upregulated in all analyzed patients but none of the cell lines. Whole-genome microarrays were performed for analysis of selected melanoma cell lines to identify potential transcriptionally regulated miRNA target genes. Using Ingenuity pathway analysis, we identified a deregulated gene network centered around microphthalmia-associated transcription factor, a transcription factor known to play a key role in melanoma development. Our findings define miRNAs and miRNA target genes that offer candidate biomarkers in human melanoma. ©2010 AACR. [less ▲]

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