Abstract

In the era of targeted therapies, patients with gynecological and urogenital malignancies have not yet been beneficiaries of this new class of therapeutical development. Prostate, bladder, kidney, ovary and cervical cancer are highly heterogeneous groups of cancer with variable response to standard chemotherapies. The high existing unmet need in treatment of this kind of cancer is reflected by the poor prognosis of patients with advanced stage disease. Long non-coding RNAs (lncRNA) are non-protein coding transcripts longer than 200 nucleotides. 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) and the functional role of these molecules outside the mitochondria is suggested by their cytoplasmic and nuclear localization. One of these transcripts, sense ncmtRNA (S-ncmtRNA) is expressed in normal proliferating cells, as well as in tumor cells but not in non-dividing cells, suggesting a role in cell cycle progression. Normal proliferating cells also express two antisense transcripts, named AS-ncmtRNA-1 and -2. Remarkably however, tumor cell lines, as well as tumor cells present in gynecological and urinary human biopsies, down-regulate the expression of AS-ncmtRNAs. Because the AsncmtRNAs are down-regulated in tumor cells, we hypothesized that these transcripts might function as unique mitochondrial-encoded tumor suppressor. In tumor cell lines of prostate, ovary, renal, bladder and cervix, we found that knocking down these transcripts in vitro with antisense oligonucleotides (ASO) induces a strong inhibition of cell proliferation, induction of caspase activation, DNA fragmentation, and inhibition of stemness, mediated by a drastic reduction in the levels of inhibitor of apoptosis survivin, which is up-regulated in practically all human cancers. The experimental evidence obtained in vitro assays, suggest that this transcripts are general target for the development of therapy mediated by antisense oligonucleotide (ASO). Therefore, we developed several xenograft models of these cancer and our results suggest a strong efficacy of the ASO therapy in vivo. Finally, we hypothesized, that the mechanism of induction of cell death, after ASO treatment, will be mediated by the generation of miRNAs targeting several mRNAs of protein involved in cell cycle control and cell survival.