Comprehensive identification of long noncoding RNAs in colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers in humans and a leading cause of cancer-related deaths worldwide. As in the case of other cancers, CRC heterogeneity leads to a wide range of clinical outcomes and complicates therapy. Over the years, multiple factors have emerged as markers of CRC heterogeneity, improving tumor classification and selection of therapeutic strategies. Understanding the molecular mechanisms underlying this heterogeneity remains a major challenge. A considerable research effort is therefore devoted to identifying additional features of colorectal tumors, in order to better understand CRC etiology and to multiply therapeutic avenues. Recently, long noncoding RNAs (lncRNAs) have emerged as important players in physiological and pathological processes, including CRC. Here we looked for lncRNAs that might contribute to the various colorectal tumor phenotypes. We thus monitored the expression of 4898 lncRNA genes across 566 CRC samples and identified 282 lncRNAs reflecting CRC heterogeneity. We then inferred potential functions of these lncRNAs. Our results highlight lncRNAs that may participate in the major processes altered in distinct CRC cases, such as WNT/ß-catenin and TGF-ß signaling, immunity, the epithelial-to-mesenchymal transition (EMT), and angiogenesis. For several candidates, we provide experimental evidence supporting our functional predictions that they may be involved in the cell cycle or the EMT. Overall, our work identifies lncRNAs associated with key CRC characteristics and provides insights into their respective functions. Our findings constitute a further step towards understanding the contribution of lncRNAs to CRC heterogeneity. They may open new therapeutic opportunities.

Portraying breast cancers with long noncoding RNAs.

Evidence is emerging that long noncoding RNAs (lncRNAs) may play a role in cancer development, but this role is not yet clear. We performed a genome-wide transcriptional survey to explore the lncRNA landscape across 995 breast tissue samples. We identified 215 lncRNAs whose genes are aberrantly expressed in breast tumors, as compared to normal samples. Unsupervised hierarchical clustering of breast tumors on the basis of their lncRNAs revealed four breast cancer subgroups that correlate tightly with PAM50-defined mRNA-based subtypes. Using multivariate analysis, we identified no less than 210 lncRNAs prognostic of clinical outcome. By analyzing the coexpression of lncRNA genes and protein-coding genes, we inferred potential functions of the 215 dysregulated lncRNAs. We then associated subtype-specific lncRNAs with key molecular processes involved in cancer. A correlation was observed, on the one hand, between luminal A-specific lncRNAs and the activation of phosphatidylinositol 3-kinase, fibroblast growth factor, and transforming growth factor-ß pathways and, on the other hand, between basal-like-specific lncRNAs and the activation of epidermal growth factor receptor (EGFR)-dependent pathways and of the epithelial-to-mesenchymal transition. Finally, we showed that a specific lncRNA, which we called CYTOR, plays a role in breast cancer. We confirmed its predicted functions, showing that it regulates genes involved in the EGFR/mammalian target of rapamycin pathway and is required for cell proliferation, cell migration, and cytoskeleton organization. Overall, our work provides the most comprehensive analyses for lncRNA in breast cancers. Our findings suggest a wide range of biological functions associated with lncRNAs in breast cancer and provide a foundation for functional investigations that could lead to new therapeutic approaches.

MicroRNAs regulate KDM5 histone demethylases in breast cancer cells.

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Alteration of miRNA levels is common in tumors and contributes to the pathogenesis of human malignancies. In the present study we examined the role played by miR-137 in breast tumorigenesis. We found miR-137 levels to be lower in breast cancer cells than in their non-tumorigenic counterparts and observed reduced proliferation and migration of breast cancer cells overexpressing miR-137. We further identified KDM5B, a histone demethylase known to be involved in breast cancer tumorigenesis, as a target of miR-137. As the involvement of histone demethylases in cancer is still poorly understood and as the role of miRNAs in controlling epigenetic mechanisms in cancer is emerging, we broadened our study to the whole KDM5 histone demethylase family to see if the genes coding for these epigenetic enzymes might be regulated by miRNAs in cancer cells. We discovered that KDM5C is overexpressed in breast cancer cells, providing evidence that miR-138 regulates its expression. We found miR-138 overexpression to affect breast cancer cell proliferation. Altogether, our findings suggest that miRNAs may regulate KDM5 histone demethylase levels in breast cancer and thereby control breast cancer cell proliferation and migration.