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.
A novel mouse model of gallbladder preneoplasia secondary to diet‐induced stones progresses in parallel with intense inflammation. Ezetimibe inhibits stone formation, inflammation, and metaplasia–dysplasia development. Aspirin does not reduce stone formation, however, ameliorates inflammation and preneoplasia onset (but only in a low‐cholesterol diet). This model recapitulates the metaplasia–dysplasia sequence observed in humans and is suitable for gallbladder carcinogenesis research.
Mitochondria are traditionally been viewed as the cell's powerhouse, generating most of its ATP. However, besides this fundamental metabolic role, mitochondria are implicated in diverse other processes, including apoptosis, inflammation and metastasis. These functions are exerted in part by the growing class of long noncoding mitochondrial RNAs (lncmtRNAs). We found that normal human proliferating cells express a family of noncoding mitochondrial RNAs (ncmtRNAs), comprised of sense (SncmtRNA) and antisense (ASncmtRNA). However, tumor cells express only sense transcripts, suggesting that ASncmtRNA downregulation as a cancer new hallmark. The few ASncmtRNAs copies in tumor cells seem essential to tumor cell viability: knockdown of these transcripts with antisense oligonucleotides (ASO) causes massive apoptotic death of tumor cells, preceded by cell cycle arrest. Preclinical assays show that systemic administration of ASO delayed tumor growth in melanoma and renal cancer models and, caused total remission in subcutaneous renal cancer tumors. The same treatment, however, does not affect normal tissue, suggesting this approach for the development of an efficient and safe therapeutic strategy for several cancer types.
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