MiR-122 significantly decreased the tumor volume and suppressed metastasis by reducing blood vessel formation. Integrated analysis combining expression array and in silico prediction revealed that miR-122 had 45 potential Alectinib ic50 mRNA targets. Thirty-two of these cellular genes have been validated by reporter assays, and shown to be involved in functional ontologies, mainly “cell morphology” and “cell movement”. Subsequent experiments illustrated that silencing of one such gene, a disintegrin and metalloprotease 17 (ADAM17), showed similar phenotypes to that when miR-122 was restored.54 Furthermore, the level of let-7g was found to be
significantly lowered in metastatic HCC compared with metastasis-free HCC.51 Transfection of let-7g significantly inhibited HCC cell migration but not invasion. While in silico prediction showed that 11 collagen genes contained 3′-UTR binding sites for let-7g, type I collagen α2 (COL1A2) was experimentally validated as a direct target. Moreover, addition of COL1A2 counteracted the inhibitory effect of let-7g on cell migration. It would therefore be suggested that Fulvestrant manufacturer let-7g suppressed HCC metastasis, at least in part, through targeting COL1A2.51 A number of miRNAs, including miR-9, miR-143, miR-30d and miR-151, have been shown to function as promoters of HCC metastasis.
In this respect, miR-9 was found to be commonly upregulated in metastatic HCC tumors.70 MiR-9 inhibition reduced SK-Hep1 cell invasion with re-expression of E-cadherin, an epithelial adhesion molecule.70 Downregulation of E-cadherin decreases the strength of cellular adhesion resulting in an increase in cell motility, which is characteristic of epithelial-mesenchymal transition (EMT).71 On the other hand, miR-143 favored the invasive and metastatic behavior of liver tumor cells in both in vitro and in vivo models, an effect exerted by targeting the fibronectin type III domain containing 3B (FNDC3B).72 MiR-143
induced by NF-κB was found to be significantly upregulated in metastatic HBV-related HCC tumors.72 Moreover, selleck chemicals llc marked upregulation of miR-30d in metastatic HCC has been shown to enhance migration and invasion of HCC cells, and to promote intrahepatic and distal pulmonary metastasis in an orthotopic mouse model.73 Luciferase activity assays have confirmed the target association of miR-30d with Galphai2 (GNAI2), a G protein α subunit that inhibits adenylate cyclase activity.73 MiR-151, located within the intronic region of FAK on Chr8q24.3, was found to be frequently overexpressed in HCC.43 Upregulation of miR-151 promoted HCC cell migration and invasion both in vitro and in vivo by targeting RhoGDP dissociation inhibitor (RhoGDIA). The RhoGTPases, including RhoA, Rac1, Cdc42, are important regulators of cell migration. RhoGDIA binds to the GDP-bound form of RhoGTPase and prevents the activation of metastasis-promoting Rho pathway.
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