期刊
ONCOGENE
卷 32, 期 4, 页码 491-501出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.61
关键词
gastric carcinoma; miR-145; metastasis; N-cadherin
资金
- National Natural Science Foundation of China [30972929, 81172351]
- Natural Science Foundation of Shandong Province of China [ZR2010HM075]
Invasion and metastasis are the major features of malignant tumors that are responsible for 90% of cancer-related deaths. Recently, microRNAs have been discovered to have a role in suppressing tumor metastasis. This study's aim was to clarify the roles of miR-145 in gastric carcinomas and its underlying molecular mechanism in regulating tumor metastasis. Here, we demonstrate a stepwise downregulation of miR-145 level in nontumorous gastric mucosa, primary gastric cancers-and their secondary metastases. In vitro analysis of miR-145's ectopic expression and loss-of-function suggests that it suppresses gastric cancer cell migration and invasion. In vivo spontaneous metastasis and experimental metastasis assay further confirm its function in suppressing the invasion-metastasis cascade, including impairing local invasion and inhibiting hematogenous metastasis in gastric cancers. Furthermore, we identified a novel mechanism of miR-145 to suppress metastasis. N-cadherin (CDH2) was proved to be a direct target of miR-145, using luciferase assay and western blot. Re-expressing N-cadherin in miR-145-transfected cells reverses their migration and invasion defects. Although not a direct target of miR-145, matrix metallopeptidase 9 (MMP9), but not MMP2, was also significantly decreased in miR-145-expressing cells. We suggest that miR-145 suppresses tumor metastasis by inhibiting N-cadherin protein translation, and then indirectly downregulates its downstream effector MMP9. Oncogene (2013) 32, 491-501; doi:10.1038/onc.2012.61; published online 27 February 2012
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