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See detailCross-Linking Ligation and Sequencing of Hybrids (qCLASH) Reveals an Unpredicted miRNA Targetome in Melanoma Cells
Kozar, Ines UL; Philippidou, Demetra UL; Margue, Christiane UL et al

in Cancers (2021)

MicroRNAs are key post-transcriptional gene regulators often displaying aberrant expression patterns in cancer. As microRNAs are promising disease-associated biomarkers and modulators of responsiveness to ... [more ▼]

MicroRNAs are key post-transcriptional gene regulators often displaying aberrant expression patterns in cancer. As microRNAs are promising disease-associated biomarkers and modulators of responsiveness to anti-cancer therapies, a solid understanding of their targetome is crucial. Despite enormous research efforts, the success rates of available tools to reliably predict microRNAs (miRNA)-target interactions remains limited. To investigate the disease-associated miRNA targetome, we have applied modified cross-linking ligation and sequencing of hybrids (qCLASH) to BRAF-mutant melanoma cells. The resulting RNA-RNA hybrid molecules provide a comprehensive and unbiased snapshot of direct miRNA-target interactions. The regulatory effects on selected miRNA target genes in predicted vs. non-predicted binding regions was validated by miRNA mimic experiments. Most miRNA–target interactions deviate from the central dogma of miRNA targeting up to 60% interactions occur via non-canonical seed pairing with a strong contribution of the 3′ miRNA sequence, and over 50% display a clear bias towards the coding sequence of mRNAs. miRNAs targeting the coding sequence can directly reduce gene expression (miR-34a/CD68), while the majority of non-canonical miRNA interactions appear to have roles beyond target gene suppression (miR-100/AXL). Additionally, non-mRNA targets of miRNAs (lncRNAs) whose interactions mainly occur via non-canonical binding were identified in melanoma. This first application of CLASH sequencing to cancer cells identified over 8 K distinct miRNA–target interactions in melanoma cells. Our data highlight the importance non-canonical interactions, revealing further layers of complexity of post-transcriptional gene regulation in melanoma, thus expanding the pool of miRNA–target interactions, which have so far been omitted in the cancer field. [less ▲]

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See detailZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas
Sommerova, Lucia; Ondrouskova, Eva; Martisova, Andrea et al

in Cancers (2020), 12

Epithelial-mesenchymal transition (EMT) is a process involved not only in morphogenesis and embryonic development, but also in cancer progression, whereby tumor cells obtain a more aggressive metastatic ... [more ▼]

Epithelial-mesenchymal transition (EMT) is a process involved not only in morphogenesis and embryonic development, but also in cancer progression, whereby tumor cells obtain a more aggressive metastatic phenotype. Anterior gradient protein 2 (AGR2) maintains the epithelial phenotype and blocks the induction of EMT, thus playing an undeniable role in tumor progression. However, the mechanism through which AGR2 expression is regulated, not only during EMT, but also in the early stages of cancer development, remains to be elucidated. In the present study, we show an inverse correlation of AGR2 with ZEB1 (zinc finger enhancer binding protein, EF1) that was verified by analysis of several independent clinical data sets of lung adenocarcinomas. We also identified the ZEB1 binding site within the AGR2 promoter region and confirmed AGR2 as a novel molecular target of ZEB1. The overexpression of ZEB1 decreased the promoter activity of the AGR2 gene, which resulted in reduced AGR2 protein level and the acquisition of a more invasive phenotype of these lung cancer cells. Conversely, silencing of ZEB1 led not only to increased levels of AGR2 protein, but also attenuated the invasiveness of tumor cells. The AGR2 knockout, vice versa, increased ZEB1 expression, indicating that the ZEB1/AGR2 regulatory axis may function in a double negative feedback loop. In conclusion, we revealed for the first time that ZEB1 regulates AGR2 at the transcriptional level, while AGR2 presence contributes to ZEB1 mRNA degradation. Thus, our data identify a new regulatory mechanism between AGR2 and ZEB1, two rivals in the EMT process, tightly associated with the development of metastasis. [less ▲]

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See detailHypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles
Walbrecq, Geoffroy; Lecha, Odile; Gaigneaux, Anthoula UL et al

in Cancers (2020)

Reduced levels of intratumoural oxygen are associated with hypoxia-induced pro-oncogenic events such as invasion, metabolic reprogramming, epithelial–mesenchymal transition, metastasis and resistance to ... [more ▼]

Reduced levels of intratumoural oxygen are associated with hypoxia-induced pro-oncogenic events such as invasion, metabolic reprogramming, epithelial–mesenchymal transition, metastasis and resistance to therapy, all favouring cancer progression. Small extracellular vesicles (EV) shuttle various cargos (proteins, miRNAs, DNA and others). Tumour-derived EVs can be taken up by neighbouring or distant cells in the tumour microenvironment, thus facilitating intercellular communication. The quantity of extracellular vesicle secretion and their composition can vary with changing microenvironmental conditions and disease states. Here, we investigated in melanoma cells the influence of hypoxia on the content and number of secreted EVs. Whole miRNome and proteome profiling revealed distinct expression patterns in normoxic or hypoxic growth conditions. Apart from the well-known miR-210, we identified miR-1290 as a novel hypoxia-associated microRNA, which was highly abundant in hypoxic EVs. On the other hand, miR-23a-5p and -23b-5p were consistently downregulated in hypoxic conditions, while the protein levels of the miR-23a/b-5p-predicted targetIPO11were concomitantly upregulated. Furthermore, hypoxic melanoma EVs exhibit a signature consisting of six proteins (AKR7A2, DDX39B, EIF3C, FARSA, PRMT5, VARS), which were significantly associated with a poor prognosis for melanoma patients, indicating that proteins and/or miRNAs secreted by cancer cells may be exploited as biomarkers. [less ▲]

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See detailPrognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges
Koncina, Eric UL; Haan, Serge UL; Rauh, Stefan et al

in Cancers (2020)

Colorectal cancer (CRC) is a leading cause of death among cancer patients. This heterogeneous disease is characterized by alterations in multiple molecular pathways throughout its development. Mutations ... [more ▼]

Colorectal cancer (CRC) is a leading cause of death among cancer patients. This heterogeneous disease is characterized by alterations in multiple molecular pathways throughout its development. Mutations in RAS, along with the mismatch repair gene deficiency, are currently routinely tested in clinics. Such biomarkers provide information for patient risk stratification and for the choice of the best treatment options. Nevertheless, reliable and powerful prognostic markers that can identify “high-risk” CRC patients, who might benefit from adjuvant chemotherapy, in early stages, are currently missing. To bridge this gap, genomic information has increasingly gained interest as a potential method for determining the risk of recurrence. However, due to several limitations of gene-based signatures, these have not yet been clinically implemented. In this review, we describe the different molecular markers in clinical use for CRC, highlight new markers that might become indispensable over the next years, discuss recently developed gene expression-based tests and highlight the challenges in biomarker research. [less ▲]

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