Non-coding mitochondrial rnas (ncmtRNAs) in gynecological and urinary malignancies: Universal targets for development of an efficient therapy?

In the era of targeted therapies, patients with gynecological and urogenital malignancies have not yet benefitted from this new class of therapeutical development. Prostate, bladder, kidney, ovary and cervical cancer are highly heterogeneous groups of cancer with variable responses to standard chemotherapies. The highly unmet need in treatment of these kinds of cancers is reflected in the poor prognosis of patients with advanced stage disease. Long non-coding RNAs (lncRNA) are non-protein coding transcripts over 200 nucleotides in length. The repertoire of lncRNA functions is rapidly expanding with defined roles in development, as mediators of mRNA decay, host genes for miRNAs, etc. Accumulating evidence indicates that aberrant expression of lncRNAs may play an important role in gynecological and urinary cancer biology. Human cells express a family of mitochondrial long non-coding RNAs (ncmtRNAs), whose functional role probably lies outside the mitochondria, based on their cytoplasmic and nuclear localization. One of these transcripts, sense ncmtRNA (SncmtRNA) is expressed in normal proliferating cells, as well as in tumour cells but not in non-dividing cells, suggesting a role in cell cycle progression. Normal proliferating cells also express two antisense transcripts, named ASncmtRNA-1 and ASncmtRNA-2. Remarkably however, tumour cell lines, as well as tumour cells present in gynecological and urinary human biopsies, downregulate the expression of AS-ncmtRNAs. Based on this differential expression pattern, we hypothesized that these transcripts might function as unique mitochondrial-encoded tumour suppressors. In tumour cell lines of prostate, ovary, kidney, bladder and cervix, we found that knocking down the AS transcripts in vitro with antisense oligonucleotides (ASO) induces a strong inhibition of cell proliferation and massive apoptotic cell death, the latter mediated by a drastic reduction in the levels of the inhibitor of apoptosis survivin. Apoptosis is reflected by caspase activation, DNA fragmentation and mitochondrial membrane potential loss, among other emblematic apoptotic traits. The treatment also strongly affects stemness in vitro and loss of migration and invasion factors. The experimental evidence we have obtained in vitro suggests that these transcripts constitute universal targets for the development of a therapy mediated by antisense oligonucleotides (ASO). Therefore, we developed several xenograft models of these cancers and our results suggest a strong efficacy of the ASO therapy in vivo. Finally, we hypothesize that the mechanism of induction of cell death, after ASO treatment, could be mediated by the generation of miRNAs targeting the mRNAs of an array of proteins involved in cell cycle control, cell survival and metastasis.