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Transcription profiling by array of human malignant melanoma cell line, A375, following interferon-gamma-induced gene transcription

ABSTRACT: MicroRNAs are major regulators of post-transcriptional gene regulation. Even small changes in miRNA levels may have profound consequences for the expression levels of target genes. Hence, miRNAs themselves need to be tightly, albeit dynamically, regulated. Here, we investigated the dynamic behaviour of miRNAs over a wide time range following transcriptional activation of melanoma cells by interferon-? (IFN-?), which activates the transcription factor STAT1. By applying several software packages for analyses, visualisation and identification of differentially expressed miRNAs derived from time-series microarray experiments, 8.9% (98) of 1102 miRNAs appeared to be directly or indirectly regulated by STAT1. Focussing on distinct dynamic expression patterns, we found that the majority of differentially expressed miRNAs were up-or down-regulated in the intermediate time range (24 h - 48 h), one (miR-27a*) was up-regulated early (already at 18 h), while none reacted late (after 72 h – 96 h). Expression of individual miRNAs was altered gradually over time or it abruptly increased between two time points. Furthermore, we have observed co-ordinated dynamic transcription of several clustered miRNAs. However, we also detected that some of those can be regulated independently of their genetic cluster. Most interestingly, several “star” or passenger strand sequences were specifically regulated over time while their “guide” strands were not.

ORGANISM(S): Homo sapiens

SUBMITTER: Reinsbach S

PROVIDER: S-ECPF-MEXP-3544 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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Project description:Skin cancer is one of the most common cancers worldwide. Melanoma accounts for ~5% of skin cancers but causes the large majority of skin cancer?related deaths. Recent discoveries have shown that the mitogen?activated protein kinase (MAPK) signaling pathway is critical for melanoma development and progression. Many oncogenic pathways that cause melanoma tumorigenesis have been identified, most of which are due to RAF/MEK/ERK (MAPK) pathway activation. However, the precise role of p38 remains unclear. Using specific short hairpin (sh) RNA to silence p38? and p38?, the present findings demonstrated that p38? was a crucial factor in regulating cell migration in the A375 melanoma cell line. Silencing p38? downregulated the expression of epithelial?mesenchymal transition markers, such as matrix metallopeptidase (MMP) 2, MMP9, twist family bHLH transcription factor 1, snail family transcriptional repressor 1 and vimentin, while mesenchymal?epithelial transition markers, such as E?cadherin, were upregulated. Of note, the results also demonstrated that p38? silencing impaired vascular endothelial growth factor expression, which regulates tumor angiogenesis. Furthermore, p38? knockdown inhibited cell proliferation in melanoma cells. In addition, silencing p38? induced senescence?like features, but not cell cycle arrest. Expression of the senescence markers p16, p21, p53 and ??galactosidase was upregulated, and an increase in the number of senescence?associated ??galactosidase?positive cells was observed in a p38? knockdown stable clone. However, no significant difference was found between control and p38? stable knockdown cells. Taken together, the present results suggested that p38? knockdown impaired migration and proliferation, and increased senescence, in A375 melanoma cells. However, p38? may not be involved in melanoma tumorigenesis. Therefore, targeting p38? may be a valuable approach towards inhibiting tumor growth and metastasis in patients with melanoma.

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Transcription profiling by array of human malignant melanoma cell line, A375, following interferon-gamma-induced gene transcription

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