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    Antisense noncoding mitochondrial RNA-2 gives rise to miR-4485-3p by Dicer processing in vitro
    (2021)
    Nicole Farfán
    ;
    Nicole Sanhueza
    ;
    Macarena Briones
    ;
    Luis O. Burzio
    ;
    Verónica A. Burzio
    <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>The antisense noncoding mitochondrial RNAs (ASncmtRNAs) derive from the mitochondrial 16S gene. Knockdown of these transcripts with chemically-modified antisense oligonucleotides induces proliferative arrest, apoptosis and invasiveness reduction in tumor but not normal cells. One of these transcripts, ASncmtRNA-2, contains the complete and identical sequence of hsa-miR-4485-3p and, upon knockdown of this transcript, there is a strong increase in levels of this miRNA, suggesting ASncmtRNA-2 as a source for miR-4485-3p, which is supported by several evidences from our group and others, in the ex vivo setting.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Here we show that incubation of in vitro-transcribed ASncmtRNA-2 with recombinant Dicer produces RNA fragments corresponding to hsa-miR-4485-3p, showing that Dicer binds to and processes ASncmtRNA-2, strongly supporting the hypothesis that ASncmtRNA-2 acts as a precursor for miR-4485-3p.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>The in vitro results presented here strengthen the hypothesis that miR-4485-3p is derived from ASncmtRNA-2 by Dicer processing. Since miR-4485-3p is classified as a tumor suppressor miRNA, this evidence strengthens the application of ASncmtRNA knockdown for cancer therapy.</jats:p> </jats:sec>
    Scopus© Citations 5  1
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    Item type:Publication,
      1  2Scopus© Citations 56
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    Targeting antisense mitochondrial noncoding RNAs induces bladder cancer cell death and inhibition of tumor growth through reduction of survival and invasion factors
    (2020)
    Vincenzo Borgna
    ;
    Lorena González-sánchez
    ;
    Francisca Guevara
    ;
    Eduardo Landerer
    ;
    Maximiliano Bendek
      10Scopus© Citations 15
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    Item type:Publication,
    Exosomes released upon mitochondrial ASncmtRNA knockdown reduce tumorigenic properties of malignant breast cancer cells
    (2020)
    Lorena González-sánchez
    ;
    Rocío Bustos
    ;
    América Campos
    ;
    Valeria Silva
    ;
    Verónica Silva
    <jats:title>Abstract</jats:title><jats:p>During intercellular communication, cells release extracellular vesicles such as exosomes, which contain proteins, ncRNAs and mRNAs that can influence proliferation and/or trigger apoptosis in recipient cells, and have been proposed to play an essential role in promoting invasion of tumor cells and in the preparation of metastatic niches. Our group proposed the antisense non-coding mitochondrial RNA (ASncmtRNA) as a new target for cancer therapy. ASncmtRNA knockdown using an antisense oligonucleotide (ASO-1537S) causes massive death of tumor cells but not normal cells and strongly reduces metastasis in mice. In this work, we report that exosomes derived from ASO-1537S-treated MDA-MB-231 breast cancer cells (Exo-1537S) inhibits tumorigenesis of recipient cells, in contrast to exosomes derived from control-ASO-treated cells (Exo-C) which, in contrast, enhance these properties. Furthermore, an <jats:italic>in vivo</jats:italic> murine peritoneal carcinomatosis model showed that Exo-1537S injection reduced tumorigenicity compared to controls. Proteomic analysis revealed the presence of Lactadherin and VE-Cadherin in exosomes derived from untreated cells (Exo-WT) and Exo-C but not in Exo-1537S, and the latter displayed enrichment of proteasomal subunits. These results suggest a role for these proteins in modulation of tumorigenic properties of exosome-recipient cells. Our results shed light on the mechanisms through which ASncmtRNA knockdown affects the preparation of breast cancer metastatic niches in a peritoneal carcinomatosis model.</jats:p>
      16Scopus© Citations 31