Oncotarget

Priority Research Papers:

Mitochondrial ASncmtRNA-1 and ASncmtRNA-2 as potent targets to inhibit tumor growth and metastasis in the RenCa murine renal adenocarcinoma model

Vincenzo Borgna _, Jaime Villegas, Verónica A. Burzio, Sebastián Belmar, Mariela Araya, Emanuel Jeldes, Lorena Lobos-González, Verónica Silva, Claudio Villota, Luciana Oliveira-Cruz, Constanza Lopez, Teresa Socias, Octavio Castillo and Luis O. Burzio

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Oncotarget. 2017; 8:43692-43708. https://doi.org/10.18632/oncotarget.18460

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Abstract

Vincenzo Borgna1,2,3, Jaime Villegas1,2,4, Verónica A. Burzio1,2,4, Sebastián Belmar2, Mariela Araya1,2,4, Emanuel Jeldes1,2,4, Lorena Lobos-González1,2, Verónica Silva1,2, Claudio Villota1,2,5, Luciana Oliveira-Cruz1,2, Constanza Lopez1,2, Teresa Socias1,2, Octavio Castillo6 and Luis O. Burzio1,2,4

1 Andes Biotechnologies SpA, Santiago, Chile

2 Fundación Ciencia & Vida, Ñuñoa, Santiago, Chile

3 Servicio de Urología, Hospital Barros Luco-Trudeau, Universidad de Santiago, Santiago, Chile

4 Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago, Chile

5 Facultad de Salud, Universidad Bernardo O Higgins, Santiago, Chile

6 Centro de Cirugía Robótica, Clínica Indisa, Santa María, Santiago, Chile

Correspondence to:

Vincenzo Borgna, email:

Verónica A. Burzio, email:

Jaime Villegas, email:

Luis O. Burzio, email:

Keywords: murine renal cancer, ncRNA, mitochondria, antisense therapy

Received: December 14, 2016 Accepted: May 28, 2017 Published: June 13, 2017

Abstract

Knockdown of antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptosis in several human and mouse tumor cell lines, but not normal cells, suggesting this approach for a selective therapy against different types of cancer. Here we show that in vitro knockdown of murine ASncmtRNAs induces apoptotic death of mouse renal adenocarcinoma RenCa cells, but not normal murine kidney epithelial cells. In a syngeneic subcutaneous RenCa model, treatment delayed and even reversed tumor growth. Since the subcutaneous model does not reflect the natural microenviroment of renal cancer, we used an orthotopic model of RenCa cells inoculated under the renal capsule. These studies showed inhibition of tumor growth and metastasis. Direct metastasis assessment by tail vein injection of RenCa cells also showed a drastic reduction in lung metastatic nodules. In vivo treatment reduces survivin, N-cadherin and P-cadherin levels, providing a molecular basis for metastasis inhibition. In consequence, the treatment significantly enhanced mouse survival in these models. Our results suggest that the ASncmtRNAs could be potent and selective targets for therapy against human renal cell carcinoma.


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