Search

Ovarian cancer (OC) is the leading cause of death in patients with gynecologic cancers. Due to late diagnosis and resistance to chemotherapy, the 5‐year survival rate in patients with OC is below 40%. We observed that UCA1, a lncRNA previously reported to play an oncogenic role in several malignancies, is overexpressed in the chemoresistant OC cell line OAW42‐R compared to their chemotherapy‐sensitive counterpart OAW42. Additionally, UCA1 overexpression was related to poor prognosis in two independent patient cohorts. Currently, the molecular mechanisms through which UCA1 acts in OC are poorly understood. We demonstrated that downregulation of the short isoform of UCA1 sensitized OC cells to cisplatin and that UCA1 acted as competing endogenous RNA to miR‐27a‐5p. Upon UCA1 downregulation, miR‐27a‐5p downregulated its direct target UBE2N leading to the upregulation of BIM, a proapoptotic protein of the Bcl2 family. The upregulation of BIM is the event responsible for the sensitization of OC cells to cisplatin. In order to model response to therapy in patients with OC, we used several patient‐derived organoid cultures, a model faithfully mimicking patient's response to therapy. Inhibition of UBE2N sensitized patient‐derived organoids to platinum salts. In conclusion, response to treatment in patients with OC is regulated by the UCA1/miR‐27a‐5p/UBE2N axis, where UBE2N inhibition could potentially represent a novel therapeutic strategy to counter chemoresistance in OC. [ABSTRACT FROM AUTHOR]

Circulating miRNAs are promising biomarkers in oncology but have not yet been implemented in the clinic given the lack of concordance across studies. In order to increase the cross-studies reliability, we attempted to reduce and to control the circulating miRNA expression variability between patients. First, to maximize profiling signals and to reduce miRNA expression variability, three isolation kits were compared and the NucleoSpin ® kit provided higher miRNA concentrations than the other widely used kits. Second, to control inter-sample variability during the profiling step, the exogenous miRNAs normalization method commonly used for RT-qPCR validation step was adapted to microarray experiments. Importantly, exogenous miRNAs presented two-fold lower inter-sample variability than the widely used endogenous miR-16-5p reflecting that the latter is subject to both biological and technical variability. Although Caenorhabditis elegans miRNAs isolation yields were heterogeneous, they correlated to each other and to their geometrical mean across samples. The normalization based on the geometrical mean of three exogenous miRNAs increased the correlation up-to 0.97 between the microarrays and individual RT-qPCR steps of circulating miRNAs expression. Overall, this new strategy open new avenue to identify reliable circulating miRNA signatures for translation into clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: The re-introduction of miRNAs with tumor-suppressor activity in cancer cells has not yet been implemented in clinical practice yet. However, the identification of miRNAs' targets and associated regulatory networks might allow the definition of new strategies using drugs whose association mimics a given miRNA's effects. We devised a multi-omics approach to precisely characterize the effects of miR-491-5p, a cytotoxic miRNA in ovarian cancer cells, and performed an integrated network analysis. We identified the already known EGFR and BCL2L1 but also EP300, CTNNB1 and several small-GTPases—either direct or indirect targets of miR-491-5p—as regulatory hubs for miR-491-5p-mediated effects. Targeting different combinations of these hubs with specific inhibitors mimic miR-491-5p-induced cytotoxicity. Pharmacological inhibitors of these targets are available for clinical use or in clinical trials; thus, this study might enable innovative therapeutic options for ovarian cancer, the leading cause of death from gynecological malignancies in developed countries. The identification of miRNAs' targets and associated regulatory networks might allow the definition of new strategies using drugs whose association mimics a given miRNA's effects. Based on this assumption we devised a multi-omics approach to precisely characterize miRNAs' effects. We combined miR-491-5p target affinity purification, RNA microarray, and mass spectrometry to perform an integrated analysis in ovarian cancer cell lines. We thus constructed an interaction network that highlighted highly connected hubs being either direct or indirect targets of miR-491-5p effects: the already known EGFR and BCL2L1 but also EP300, CTNNB1 and several small-GTPases. By using different combinations of specific inhibitors of these hubs, we could greatly enhance their respective cytotoxicity and mimic the miR-491-5p-induced phenotype. Our methodology thus constitutes an interesting strategy to comprehensively study the effects of a given miRNA. Moreover, we identified targets for which pharmacological inhibitors are already available for a clinical use or in clinical trials. This study might thus enable innovative therapeutic options for ovarian cancer, which remains the leading cause of death from gynecological malignancies in developed countries. [ABSTRACT FROM AUTHOR]

With 240,000 new cases and 152,000 deaths per year, ovarian cancer is the leading cause of death from gynecologic malignancies. Late diagnosis because of asymptomatic development in early stages and resistance to existing treatments are the major causes of therapeutic failure in ovarian cancer. The recent discovery of tens of thousands of long non-coding RNAs and their action as oncogenes or tumor suppressors in pathways matching all the hallmarks of cancer in most – if not all – malignancies have attracted attention of the scientific community. A growing number of studies have implicated lncRNAs in diverse aspects of ovarian carcinoma biology. We present lncRNAs which have been involved in response to the different drugs currently used for the treatment of ovarian cancers, from first-line platinum salts and taxanes to the newly available PARP inhibitors. The data already available supports the potential use of several lncRNAs, alone or in combination with other molecules, as potential biomarkers for the prediction of response to treatment. Understanding the determinants of their action might reveal new potential therapeutic targets. • Ovarian cancer is the leading cause of death from gynecological malignancies. • Resistance to treatment is the major cause of therapeutic failure. • LncRNAs act as oncogene or tumor suppressors and are involved in the response to treatment. • LncRNAs expression levels might predict response to treatment. • Understanding lncRNAs modes of action could reveal innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]