Department of Pathology, Qilu Hospital, Shandong University, Shandong, PR China.
Oncogene. 2013 Jan 24;32(4):491-501. doi: 10.1038/onc.2012.61. Epub 2012 Feb 27.
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.
侵袭和转移是恶性肿瘤的主要特征，也是导致 90%癌症相关死亡的原因。最近，人们发现 microRNAs 在抑制肿瘤转移中发挥作用。本研究旨在阐明 miR-145 在胃癌中的作用及其在调节肿瘤转移中的潜在分子机制。在这里，我们证明 miR-145 水平在非肿瘤性胃黏膜、原发性胃癌及其继发转移中呈逐步下调。miR-145 异位表达和功能丧失的体外分析表明，它抑制胃癌细胞的迁移和侵袭。体内自发性转移和实验性转移实验进一步证实了它在抑制侵袭-转移级联中的功能，包括削弱局部侵袭和抑制胃癌的血源性转移。此外，我们发现了 miR-145 抑制转移的一种新机制。利用荧光素酶报告基因检测和 Western blot 实验证实 N-钙黏蛋白（CDH2）是 miR-145 的直接靶标。在转染 miR-145 的细胞中重新表达 N-钙黏蛋白可逆转其迁移和侵袭缺陷。虽然不是 miR-145 的直接靶标，但基质金属蛋白酶 9（MMP9），而不是 MMP2，在 miR-145 表达细胞中也显著减少。我们认为，miR-145 通过抑制 N-钙黏蛋白蛋白翻译来抑制肿瘤转移，然后间接下调其下游效应因子 MMP9。
