MiRNA-516a promotes bladder cancer metastasis by inhibiting MMP9 protein degradation via the AKT/FOXO3A/SMURF1 axis.
MiRNA-516a promotes bladder cancer metastasis by inhibiting MMP9 protein degradation via the AKT/FOXO3A/SMURF1 axis.
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MiRNA-516a 通过 AKT/FOXO3A/SMURF1 轴抑制 MMP9 蛋白降解，促进膀胱癌转移
DOI：
10.1002/ctm2.263
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发表时间：
2020-12
影响因子：
10.6
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Chang Y;Jin H;Li H;Ma J;Zheng Z;Sun B;Lyu Y;Lin M;Zhao H;Shen L;Zhang R;Wu S;Lin W;Lu Y;Xie Q;Zhang G;Huang X;Huang H
转移是膀胱癌（BC）患者死亡的主要原因。然而，目前可用的治疗方法对转移性乳腺癌影响甚微。此外，传统的分级和分期识别转移性乳腺癌的能力有限。越来越多的证据表明microRNA的异常表达与肿瘤进展密切相关。迄今为止，许多miRNA已被确定为癌症诊断和治疗的分子靶点。本研究重点关注 miR-516a-5p (miR-516a) 在 BC 中的作用。使用分子细胞生物学和生物化学方法和技术检测 MiR-516a 表达及其下游信号通路。使用新鲜的临床BC组织来研究不同miR-516a表达的患者的临床病理特征。在体内和体外测试了 BC 中 miR-516a 的生物学功能。 BC 患者中更具侵袭性的 BC 表型与 miR-516a 过表达显着正相关。 MiR-516a 抑制显着降低体外和体内 BC 细胞的侵袭和迁移。此外，miR-516a通过激活AKT/Forkhead box O3信号通路减弱PH结构域富含亮氨酸重复的蛋白磷酸酶2蛋白的表达，并抑制SMAD特异性E3泛素蛋白连接酶1转录，从而稳定MMP9并减缓其蛋白酶体降解，最终促进BC运动和侵袭。我们的研究结果揭示了 miR-516a 在促进 BC 转移中的关键功能，并阐明了所涉及的分子机制，表明 miR-516a 可能是 BC 的一个有前途的新型诊断和治疗靶点。首次揭示了 miR-516a 在膀胱癌转移中关键作用的潜在机制。 MiR-516a 通过靶向 PHLPP2 并随后抑制 SMURF1 介导的 MMP9 蛋白降解来促进人膀胱癌细胞的迁移和侵袭。基于 miR-516a 在膀胱癌中的转移作用，我们的研究结果为膀胱癌治疗提供了有希望的靶点。
Metastasis is the leading cause of death in patients with bladder cancer (BC). However, current available treatments exert little effects on metastatic BC. Moreover, traditional grading and staging have only a limited ability to identify metastatic BC. Accumulating evidence indicates that the aberrant expression of microRNA is intimately associated with tumor progression. So far, many miRNAs have been identified as molecular targets for cancer diagnosis and therapy. This study focused on the role of miR‐516a‐5p (miR‐516a) in BC. MiR‐516a expression and its downstream signaling pathway were detected using molecular cell biology and biochemistry approaches and techniques. Fresh clinical BC tissue was used to study the clinicopathological characteristics of patients with different miR‐516a expression. The biological functions of miR‐516a in BC were tested both in vivo and in vitro. A more invasive BC phenotype was significantly and positively correlated with miR‐516a overexpression in BC patients. MiR‐516a inhibition significantly decreased BC cell invasion and migration in vitro and in vivo. Furthermore, miR‐516a attenuated the expression of PH domain leucine‐rich repeat‐containing protein phosphatase 2 protein and inhibited SMAD‐specific E3 ubiquitin protein ligase 1 transcription by activating the AKT/Forkhead box O3 signaling pathway, which stabilized MMP9 and slowed down its proteasomal degradation, ultimately promoting BC motility and invasiveness. Our findings reveal the crucial function of miR‐516a in promoting BC metastasis, and elucidate the molecular mechanism involved, suggesting that miR‐516a may be a promising novel diagnostic and therapeutic target for BC. For the first time, the potential mechanisms underlying the critical role of miR‐516a in bladder cancer metastasis is revealed. MiR‐516a promotes migration and invasion of human bladder cancer cells by targeting PHLPP2 and subsequently inhibiting SMURF1‐mediated MMP9 protein degradation. Based on the metastatic role of miR‐516a in bladder cancer, our findings provide promising targets for bladder cancer therapy.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
--
作者：
Jin H;Yu Y;Hu Y;Lu C;Li J;Gu J;Zhang L;Huang H;Zhang D;Wu XR;Gao J;Huang C
通讯作者：
Huang C
贯穿历史：PHLPP磷酸酶生命的十年。
影响因子：
3.9
作者：
Grzechnik AT;Newton AC
通讯作者：
Newton AC
MIR516A 在人膀胱癌中的致癌作用是通过其减弱的 PHLPP2 表达和 BECN1 依赖性自噬介导的
影响因子：
13.3
作者：
Jin H;Ma J;Xu J;Li H;Chang Y;Zang N;Tian Z;Wang X;Zhao N;Liu L;Chen C;Xie Q;Lu Y;Fang Z;Huang X;Huang C;Huang H
通讯作者：
Huang H
影响因子：
4.4
作者：
Anderson, MJ;Viars, CS;Arden, KC
通讯作者：
Arden, KC