Applying the non-coding RNA links with cancer
Recent discoveries show that miRNAs regulate gene expression at the post-transcriptional level, between transcription and translation of the gene. They do not code for proteins but exert their regulatory function by binding onto the messenger RNA (mRNA) transcript. Non-coding RNAs (ncRNAs) such as miRNAs and long ncRNAs, have a key role in the aetiology and/or progression of human cancer. The specificity and potency of some miRNAs could also be exploited in therapy. The 'MicroRNAs and cancer: From bench to bedside' (ONCOMIRS) project worked on the identification of novel key components of the miRNA-processing machine and their role in carcinogenesis. Another important objective was the identification of novel putative cancer-causing ncRNAs. Through protein-complex purification and mass spectrometry analyses, many factors involved in the process of the miRNA-processing machine have been identified. In particular, those linked with cancer development have been reported. Truncating mutations in the TARBP2 gene shorten the Dicer-binding protein TRBP, which affects miRNA processing and Dicer function, thus promoting tumour development. Dicer and other miRNA-processing enzymes may therefore be important in cancer prognosis. ONCOMIRS researchers showed that while a decrease in Dicer expression increases the transforming potential of cancer cell lines, complete silencing is not tolerated by most cancer cells. The scientists generated new microarray platforms based on locked nucleic acid (LNA) technology. Attempts were made to validate single miRNA–mRNA interactions using LNA oligonucleotides that bind specifically to sequences encompassing miRNA target sites within mRNAs. These so-called target site blockers have given very promising results and are now commercially available. A new generation of miRNA mimics and antisense therapeutics has also been developed. The researchers tested and optimised their biostability, cytotoxicity and electropulsation-based delivery in vivo. Electrotransfer of miRNA inhibitors offers a new avenue for anti-cancer (retinoblastoma and glioblastoma) therapy. The results from the efforts of this consortium unveiled novel functions of ncRNAs in normal and pathological processes. Scientifically, the research in the consortium is of outmost importance for understanding the roles of ncRNAs in pathological processes such as cancer.
