Sun De-Kang, Wang Jian-Ming, Zhang Peng, Wang Yong-Qiang
Cell Physiol Biochem. 2015;37(6):2366-74. doi: 10.1159/000438590. Epub 2015 Dec 7.
BACKGROUND/AIMS: The cases of bladder cancer (BC) with poor prognosis largely result from the distal metastases of the primary tumor. Since microRNAs (miRNAs) play critical roles during cancer metastases, determination of the involved miRNAs in the regulation of the metastases of BC may provide novel therapeutic targets for BC treatment. Here, we aimed to study the role of miR-138 in regulation of BC cell invasion and metastases.
We analyzed the levels of miR-138 and ZEB2, a key factor that regulates cancer cell invasion, in the BC specimens from the patients. We also studied the correlation between miR-138 and ZEB2. We performed bioinformatics analyses on the binding of miR-138 to the 3'-UTR of ZEB2 mRNA, and verified the biological effects of this binding through promoter luciferase reporter assay. The effects of miR-138-modification on BC cell invasion were evaluated in a transwell cell invasion assay and a scratch would healing assay.
We found that the levels of miR-138 were significantly decreased and the levels of ZEB2 were significantly increased in BC specimens, compared to the paired normal bladder tissue. Metastatic BC appeared to contained lower levels of miR-138. Moreover, miR-138 and ZEB2 inversely correlated in BC specimens. Bioinformatics analyses showed that miR-138 targeted the 3'-UTR of ZEB2 mRNA to inhibit its translation. Furthermore, miR-138 overexpression inhibited ZEB2-mediated cell invasion and metastases, while miR-138 depletion increased ZEB2-mediated cell invasion and metastases in BC cells.
Suppression of miR-138 in BC cells may promote ZEB2-mediated cancer invasion and metastases. Thus, miR-138 appears to be an intriguing therapeutic target to prevent metastases of BC.
背景/目的：预后较差的膀胱癌（BC）病例主要源于原发肿瘤的远处转移。由于微小RNA（miRNA）在癌症转移过程中起关键作用，确定参与膀胱癌转移调控的miRNA可能为膀胱癌治疗提供新的治疗靶点。在此，我们旨在研究miR-138在调控膀胱癌细胞侵袭和转移中的作用。
我们分析了患者膀胱癌标本中miR-138和ZEB2（一种调节癌细胞侵袭的关键因子）的水平。我们还研究了miR-138与ZEB2之间的相关性。我们对miR-138与ZEB2 mRNA的3'-UTR的结合进行了生物信息学分析，并通过启动子荧光素酶报告基因检测验证了这种结合的生物学效应。在Transwell细胞侵袭试验和划痕愈合试验中评估了miR-138修饰对膀胱癌细胞侵袭的影响。
我们发现，与配对的正常膀胱组织相比，膀胱癌标本中miR-138水平显著降低，ZEB2水平显著升高。转移性膀胱癌似乎含有较低水平的miR-138。此外，在膀胱癌标本中miR-138与ZEB2呈负相关。生物信息学分析表明，miR-138靶向ZEB2 mRNA的3'-UTR以抑制其翻译。此外，miR-138过表达抑制ZEB2介导的细胞侵袭和转移，而miR-138缺失则增加ZEB2介导的膀胱癌细胞侵袭和转移。
膀胱癌细胞中miR-138的抑制可能促进ZEB2介导的癌症侵袭和转移。因此，miR-138似乎是预防膀胱癌转移的一个有吸引力的治疗靶点。
