ABSTRACT
Our study employs pooled CRISPR screens, integrating 2D and 3D culture models, to identify miRNAs critical in Breast Cancer (BC) tumoursphere formation. These screens combine with RNA-seq experiments allowing identification of miRNA signatures and targets essential for tumoursphere growth. miR-4787-3p exhibits significant up-regulation in BC, particularly in basal-like BCs, suggesting its association with aggressive disease. Surprisingly, despite its location within the 5'UTR of a protein coding gene, which defines DROSHA-independent transcription start site (TSS)-miRNAs, we find it dependant on both DROSHA and DICER1 for maturation. Inhibition of miR-4787-3p hinders tumoursphere formation, highlighting its potential as a therapeutic target in BC. Our study proposes elevated miR-4787-3p expression as a potential prognostic biomarker for adverse outcomes in BC. We find that protein-coding genes positively selected in the CRISPR screens are enriched of miR-4787-3p targets. Of these targets, we select ARHGAP17, FOXO3A, and PDCD4 as known tumour suppressors in cancer and experimentally validate the interaction of miR-4787-3p with their 3'UTRs. Our work illuminates the molecular mechanisms underpinning miR-4787-3p's oncogenic role in BC. These findings advocate for clinical investigations targeting miR-4787-3p and underscore its prognostic significance, offering promising avenues for tailored therapeutic interventions and prognostic assessments in BC.
Subject(s)
Breast Neoplasms , MicroRNAs , Humans , MicroRNAs/genetics , MicroRNAs/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Female , Gene Expression Regulation, Neoplastic , Transcription Initiation Site , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Cell Proliferation/genetics , Cell Line, Tumor , Ribonuclease III/genetics , Ribonuclease III/metabolism , Clustered Regularly Interspaced Short Palindromic Repeats , Spheroids, Cellular/pathology , DEAD-box RNA HelicasesABSTRACT
We are delighted to share with you our thirteenth Journal Club and highlight some of the most interesting papers published recently [...].
ABSTRACT
We are delighted to share with you our twelfth Journal Club and highlight some of the most interesting papers published recently [...].
ABSTRACT
Breast cancer affects millions of women each year. Despite recent advances in targeted treatments breast cancer remains a significant threat to women's health. In recent years the development of high-throughput sequencing technologies has advanced the field of transcriptomics shedding light on the role of non-coding RNAs (ncRNAs), including long ncRNAs (lncRNAs), in human cellular function and disease. LncRNAs are classified as transcripts longer than 200nt with no coding potential. These transcripts constitute a diverse group of regulatory molecules essential to the modulation of crucial cellular processes, which dysregulation of leads to disease. LncRNAs exert their regulatory functions through their sequences and by forming complex secondary and tertiary structures that interact with other transcripts, chromatin and/or proteins. Numerous studies have provided evidence of the involvement of LncRNAs in tumor development and disease progression. They possess multiple characteristics that make them novel therapeutic and diagnostic targets. Indeed, the discovery of a novel mechanism by which lncRNAs associated with proteins can induce the formation of phase-separated droplets broadens our understanding of the spatiotemporal control of cellular processes and opens up developing a new treatment. Nevertheless, the role and the molecular mechanisms of many lncRNAs in the regulation of cellular processes and cancer still remain elusive. This is due to the absence of a thorough characterization of the regulatory role of their loci and the functional impact of their aberrations in cancer biology. Here, we present some of the latest advances concerning the role of LncRNAs in breast cancer.
Subject(s)
Breast Neoplasms , RNA, Long Noncoding , Humans , Female , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Breast Neoplasms/genetics , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Disease ProgressionABSTRACT
We are delighted to share with you our seventh Journal Club and highlight some of the most interesting papers published recently [...].
