Chang Yuanyuan, Jin Honglei, Li Hongyan, Ma Jiugao, Zheng Zhijian, Sun Binuo, Lyu Yiting, Lin Mengqi, Zhao He, Shen Liping, Zhang Ruirui, Wu Shuilian, Lin Weiwei, Lu Yongyong, Xie Qipeng, Zhang Gang, Huang Xing, Huang Haishan
Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China.
The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
Clin Transl Med. 2020 Dec;10(8):e263. doi: 10.1002/ctm2.263.
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.
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BC的效果甚微。此外，传统的分级和分期对转移性BC的识别能力有限。越来越多的证据表明，微小RNA的异常表达与肿瘤进展密切相关。到目前为止，许多微小RNA已被确定为癌症诊断和治疗的分子靶点。本研究聚焦于miR-516a-5p（miR-516a）在BC中的作用。
采用分子细胞生物学和生物化学方法及技术检测miR-516a的表达及其下游信号通路。使用新鲜的临床BC组织研究不同miR-516a表达患者的临床病理特征。在体内和体外测试miR-516a在BC中的生物学功能。
在BC患者中，侵袭性更强的BC表型与miR-516a过表达显著正相关。抑制miR-516a可显著降低BC细胞在体外和体内的侵袭和迁移能力。此外，miR-516a通过激活AKT/叉头框O3信号通路减弱富含脯氨酸结构域亮氨酸重复蛋白磷酸酶2蛋白的表达，并抑制SMAD特异性E3泛素蛋白连接酶1的转录，从而稳定MMP9并减缓其蛋白酶体降解，最终促进BC的运动性和侵袭性。
我们的研究结果揭示了miR-516a在促进BC转移中的关键作用，并阐明了其涉及的分子机制，表明miR-516a可能是BC一个有前景的新型诊断和治疗靶点。
