Transforming growth factor-β receptor II was identified as the target for miR-370, and a reverse correlation was found between miR-370 expression and transforming growth factor-β receptor II immunoreactivity [15]. MiR-148a expression was suppressed in GC specimens, its overexpression decreased, and its inhibition increased migration and invasion in GC cells [16]. More importantly, the formation of lung metastasis was drastically reduced when MGC-803 cells stably expressed miR-148a. Rho-associated coiled-coil containing protein kinase 1 (ROCK1) was identified selleck screening library as direct target of miR-148a, and ROCK1 expression was inversely correlated
with miR-148 levels in human GC tissues [17]. Another important miRNA for invasion and metastasis is miR-335, which was frequently down-regulated in GC cells [18]. When overexpressed, it inhibited invasion and metastasis but had no effect on proliferation. Furthermore, injection of cells that stably expressed miR-335 resulted in
significantly less lung metastases in mice. Specificity protein 1 and Bcl-w were identified as targets of miR-335 [18]. Other miRNAs that were recently found to be down-regulated in GC and that suppressed invasion and metastasis were miR-610 and miR-145 [19, 20]. MiR-610 targeted vasodilator-stimulated phosphoprotein and was itself regulated by selleck compound EGF [19]. N-cadherin was a direct target of miR-145, and matrix metallopeptidase-9 was indirectly targeted through N-cadherin [20]. One important aspect of invasion and metastasis is the epithelial-mesenchymal transition (EMT). The miR-200 family was found independently in two studies to be of major importance in EMT in GC.
Kurashige et al. [21] reported a strong correlation between miR-200b and E-cadherin, and an inverse correlation between miR-200b and ZEB2, a known transcriptional repressor of E-cadherin. MiR-200b was found to target ZEB2 directly, and overexpression of miR-200b suppressed proliferation, migration, and invasion, as well as a fibroblast-like morphology of GC cells [21]. The regulation 上海皓元 of miR-200b/a itself was found to be dependent on Smad3, which was shown to bind to the promoter of miR-200b/a where it acted as a transcriptional activator [22]. High levels of miR-27 in gastric tumors on the other hand led to increases in ZEB1, ZEB2, Slug, and vimentin and to low levels of E-cadherin [23]. Invasion was promoted by miR-27 overexpression. The promotion of EMT by miR-27 was via the Wnt pathway, and Apc was shown to be a direct target of miR-27 [23]. Balance of cell growth and cell death dictates the growth potential of the tumor and regulation of apoptosis by miRNAs has been well established. Recently, miR-409-3p emerged as an important regulator of proliferation, apoptosis, and invasion and metastasis in GC [24, 16]. It was repressed in GC specimens and cells lines. Overexpression of miR-409-3p led to decreased migration and invasion in cell lines and to reduced pulmonary metastases and peritoneal dissemination in nude mice [16].
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