title: Targeting antisense mitochondrial ncRNAs inhibits murine melanoma tumor growth and metastasis through reduction in survival and invasion factors.
abstract: We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro-survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy.
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.|Facultad de Medicina, Universidad de Chile, Independencia, Santiago, Chile.
authors: Lorena
authors: L
authors: Lobos-González
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.
authors: Verónica
authors: V
authors: Silva
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.
authors: Mariela
authors: M
authors: Araya
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.|Present address: Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Franko
authors: F
authors: Restovic
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.
authors: Javiera
authors: J
authors: Echenique
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.
authors: Luciana
authors: L
authors: Oliveira-Cruz
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.|Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile.
authors: Christopher
authors: C
authors: Fitzpatrick
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.
authors: Macarena
authors: M
authors: Briones
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.|Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile.
authors: Jaime
authors: J
authors: Villegas
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.|Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile.
authors: Claudio
authors: C
authors: Villota
authors: Andes Biotechnologies SpA, Santiago, Chile.|Facultad de Salud, Deporte y Recreación, Universidad Bernardo O'Higgins, Santiago, Chile.
authors: Soledad
authors: S
authors: Vidaurre
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.|Servicio de Urología, Hospital Barros-Lucco-Trudeau, Santiago, Chile.
authors: Vincenzo
authors: V
authors: Borgna
authors: Clínica Alemana, Santiago, Chile.
authors: Miguel
authors: M
authors: Socias
authors: Fundación Ciencia & Vida, Santiago, Chile.
authors: Sebastián
authors: S
authors: Valenzuela
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.
authors: Constanza
authors: C
authors: Lopez
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.
authors: Teresa
authors: T
authors: Socias
authors: Fundación Ciencia & Vida, Santiago, Chile.
authors: Manuel
authors: M
authors: Varas
authors: Facultad de Medicina, Universidad de Chile, Independencia, Santiago, Chile.
authors: Jorge
authors: J
authors: Díaz
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.|Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile.
authors: Luis O
authors: LO
authors: Burzio
authors: Andes Biotechnologies SpA, Santiago, Chile.|Fundación Ciencia & Vida, Santiago, Chile.|Facultad de Ciencias Biológicas, Universidad Andrés Bello, República, Santiago, Chile.
authors: Verónica A
authors: VA
authors: Burzio
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D008546:Melanoma, Experimental / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000473:pathology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D022661:RNA, Untranslated / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000473:pathology / Q000628:therapy*; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D016376:Oligonucleotides, Antisense; D022661:RNA, Untranslated; D012097:Repressor Proteins; D000077022:Survivin
keywords: antisense therapy; melanoma; metastasis; mitochondria; noncoding RNA