Targeting antisense mitochondrial noncoding RNAs induces bladder cancer cell death and inhibition of tumor growth through reduction of survival and invasion factors
Targeting antisense mitochondrial noncoding RNAs induces bladder cancer cell death and inhibition of tumor growth through reduction of survival and invasion factors
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DOI：
10.7150/jca.38880
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Villegas, Jaime
中科院分区：
文献类型：
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作者：
Borgna, Vincenzo;Lobos-Gonzalez, Lorena;Villegas, Jaime
反义非编码线粒体rna （ASncmtRNAs）的敲低可诱导几种人类肿瘤细胞系的凋亡死亡，而不是正常细胞，支持针对不同类型癌症的选择性治疗。在这项工作中，我们评估了asncmtrna敲低对膀胱癌（BCa）的影响。我们用针对人asncmtrna的特异性反义寡核苷酸Andes-1537S转染了BCa细胞系UMUC-3、RT4和T24。敲低诱导了三种细胞系细胞增殖的强烈抑制和细胞死亡的增加。在UMUC-3细胞中观察到，处理引发细胞凋亡，线粒体膜电位和膜联蛋白V染色丧失，procaspase-3活化，抗凋亡因子survivin和Bcl-xL下调。处理还抑制细胞侵袭和球体形成，并抑制N-cadherin和mmp11。与生理盐水对照相比，Andes-1537S在NOD/SCID小鼠皮下异种移植UMUC-3肿瘤的体内治疗诱导肿瘤生长抑制。类似地，Andes-1537S治疗高级别膀胱癌PDX可显著抑制肿瘤生长。我们的研究结果表明，asncmtrna可能是膀胱癌辅助治疗的有效靶点。
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.