J Cancer 2020; 11(7):1780-1791. doi:10.7150/jca.38880 This issue

Research Paper

Targeting antisense mitochondrial noncoding RNAs induces bladder cancer cell death and inhibition of tumor growth through reduction of survival and invasion factors

Vincenzo Borgna1,2,3#✉, Lorena Lobos-González#4, Francisca Guevara1,5, Eduardo Landerer6, Maximiliano Bendek1, Rodolfo Ávila1, Verónica Silva1, Claudio Villota7, Mariela Araya1,8, Alexis Rivas1, Constanza López1, Teresa Socias1, Jorge Castillo9, Luis Alarcón3, Luis O. Burzio1,5,8, Verónica A. Burzio1,5,8, Jaime Villegas1,5,8*✉

1. Fundación Ciencia & Vida,
2. Facultad de Medicina, Universidad De Santiago,
3. Servicio de Urología, Hospital Barros Luco-Trudeau,
4. Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo,
5. Andes Biotechnologies SpA,
6. Facultad de Medicina, Universidad San Sebastián,
7. Escuela de Nutrición y Dietética, Facultad de Salud, Universidad Bernardo O'Higgins,
8. Facultad de Ciencias de la Vida, Universidad Andrés Bello,
9. Servicio de Anatomía Patológica, Hospital Barros Luco-Trudeau. Santiago, Chile.
*Present Address: Centro de Medicina Veterinaria. Camino Lo Pinto s/n. Colina. Universidad Andrés Bello.
# Vincenzo Borgna and Lorena Lobos-Gonzales contributed equally to this work.

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Borgna V, Lobos-González L, Guevara F, Landerer E, Bendek M, Ávila R, Silva V, Villota C, Araya M, Rivas A, López C, Socias T, Castillo J, Alarcón L, Burzio LO, Burzio VA, Villegas J. Targeting antisense mitochondrial noncoding RNAs induces bladder cancer cell death and inhibition of tumor growth through reduction of survival and invasion factors. J Cancer 2020; 11(7):1780-1791. doi:10.7150/jca.38880. Available from https://www.jcancer.org/v11p1780.htm

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Knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, supporting a selective therapy against different types of cancer. In this work, we evaluated the effects of knockdown of ASncmtRNAs on bladder cancer (BCa). We transfected the BCa cell lines UMUC-3, RT4 and T24 with the specific antisense oligonucleotide Andes-1537S, targeted to the human ASncmtRNAs. Knockdown induced a strong inhibition of cell proliferation and increase in cell death in all three cell lines. As observed in UMUC-3 cells, the treatment triggered apoptosis, evidenced by loss of mitochondrial membrane potential and Annexin V staining, along with activation of procaspase-3 and downregulation of the anti-apoptotic factors survivin and Bcl-xL. Treatment also inhibited cell invasion and spheroid formation together with inhibition of N-cadherin and MMP 11. In vivo treatment of subcutaneous xenograft UMUC-3 tumors in NOD/SCID mice with Andes-1537S induced inhibition of tumor growth as compared to saline control. Similarly, treatment of a high-grade bladder cancer PDX with Andes-1537S resulted in a strong inhibition of tumor growth. Our results suggest that ASncmtRNAs could be potent targets for bladder cancer as adjuvant therapy.

Keywords: bladder cancer, antisense therapy, noncoding RNA, apoptosis