Invasive bladder cancer (BC) is one of the most lethal malignant urological tumors. Although miR-200a has been reported as an onco-miRNA that targets the PTEN gene in endometrioid carcinoma, its biological significance in BC invasion has been poorly explored. In the current study, we found that miR-200a was markedly overexpressed in both human BC tissues and BBN-induced muscle-invasive BC tissues. We further showed that miR-200a overexpression specifically promoted human BC cell invasion, but not migration, via transcriptional upregulation of matrix metalloproteinase (MMP)-2. Mechanistic studies indicated that the increased phosphorylation of c-Jun mediated the increasing levels of MMP-2 mRNA transcription. Further investigation revealed that Dicer was decreased in miR-200a overexpressed BC cells; this resulted in inhibition of miR-16 maturation and consequently led to increased JNK2 protein translation and c-Jun activation. Taken together, the studies here showed that miR-200a overexpression inhibited Dicer expression, in turn, resulted in inhibition of miR-16 maturation, leading to upregulation of JNK2 expression, c-Jun phosphorylation, MMP-2 transcription and, ultimately, BC invasion. Collectively, these results demonstrate that miR-200a is an onco-miRNA that is a positive regulator for BC invasion. This finding could be very useful in the ongoing development of new strategies to treat invasive BC patients.

中文翻译：

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过表达的 miR-200a 通过直接调节 Dicer/miR-16/JNK2/MMP-2 轴促进膀胱癌侵袭。

浸润性膀胱癌（BC）是最致命的泌尿系统恶性肿瘤之一。尽管 miR-200a 已被报道为靶向子宫内膜样癌中 PTEN 基因的 onco-miRNA，但其在 BC 侵袭中的生物学意义尚未得到很好的探索。在目前的研究中，我们发现 miR-200a 在人类 BC 组织和 BBN 诱导的肌肉侵袭性 BC 组织中均显着过表达。我们进一步表明，通过基质金属蛋白酶 (MMP)-2 的转录上调，miR-200a 过表达特异性地促进了人类 BC 细胞的侵袭，而不是迁移。机制研究表明，c-Jun 磷酸化的增加介导了 MMP-2 mRNA 转录水平的增加。进一步的研究表明，在 miR-200a 过表达的 BC 细胞中，Dicer 减少。这导致 miR-16 成熟的抑制，从而导致 JNK2 蛋白翻译和 c-Jun 激活增加。总之，这里的研究表明，miR-200a 过表达抑制 Dicer 表达，进而抑制 miR-16 成熟，导致 JNK2 表达、c-Jun 磷酸化、MMP-2 转录上调，并最终导致 BC 入侵. 总的来说，这些结果表明 miR-200a 是一种肿瘤 miRNA，是 BC 侵袭的正调节因子。这一发现可能对正在进行的治疗侵袭性 BC 患者的新策略的开发非常有用。导致 JNK2 表达、c-Jun 磷酸化、MMP-2 转录和最终 BC 侵袭的上调。总的来说，这些结果表明 miR-200a 是一种肿瘤 miRNA，是 BC 侵袭的正调节因子。这一发现可能对正在进行的治疗侵袭性 BC 患者的新策略的开发非常有用。导致 JNK2 表达、c-Jun 磷酸化、MMP-2 转录和最终 BC 侵袭的上调。总的来说，这些结果表明 miR-200a 是一种肿瘤 miRNA，是 BC 侵袭的正调节因子。这一发现可能对正在进行的治疗侵袭性 BC 患者的新策略的开发非常有用。