Additionally, miR-195 down-regulation led to increases in VAV2 and CDC42 expression, which stimulated VAV2/Rac1/CDC42 signaling and lamellipodia formation and thereby facilitated the metastasis of HCC cells. Conclusion: miR-195 deregulation contributes to angiogenesis and metastasis in HCC. The restoration of miR-195 expression may be a promising strategy for HCC therapy. (Hepatology 2013;58:642-653) Globally, hepatocellular carcinoma (HCC) is a common and highly lethal malignancy. Active angiogenesis and frequent

metastasis are responsible for rapid recurrence and poor survival of HCC. Therefore, identifying molecules that can Selleckchem Fulvestrant suppress angiogenesis and metastasis may provide novel targets for HCC therapies. MicroRNAs (miRNAs) constitute a class of endogenous

small noncoding RNAs that suppress protein expression by base-pairing with the 3′-untranslated regions (UTRs) of target messenger RNA (mRNA). miRNAs have been demonstrated to interact with various components of multiple cellular signaling pathways and to participate in a wide Alvelestat cost range of physiological and pathological processes, including tumorigenesis. Increasing evidence suggests that the dysregulation of miRNAs plays an important role in HCC development.[1-3] To date, a few miRNAs have been characterized to have proangiogenic (miR-221[4]) or antiangiogenic (miR-122,[5] miR-29b,[6] and miR-214[7]) activities or to possess prometastatic (miR-151,[8] miR-30d,[9] miR-210,[10] and miR-135a[11]) or antimetastatic (miR-122,[12] miR-124,[13] miR-139,[14] miR-125b,[15] miR-29b,[6] and miR-7[16]) functions in HCC. Oxalosuccinic acid miR-195 is down-regulated frequently in multiple cancer types, including

HCC.[17-21] Studies from different groups have indicated a growth-suppressive function of miR-195.[17, 18, 21, 22] miR-195 has been shown to block the G1/S transition of the cell cycle by targeting CCND1/3, CDK4/6, and E2F3[17, 21] and to promote apoptosis by suppressing the expression of BCL2 and BCL-w.[18, 22] However, whether the dysregulation of miR-195 contributes to tumor angiogenesis or metastasis remains unclear. To date, only a few reports have explored the relationship of miR-195 to metastasis. Two research groups have employed the in vitro transwell system and disclosed that miR-195 might suppress the invasion of glioblastoma and breast cancer cells by targeting CCND3 and RAF1, respectively.[19, 21] In a study of miRNA profiling, miR-195 was down-regulated significantly in primary HCC tissues and tended to decrease further in portal vein tumor thrombi.[23] Clearly, more extensive investigations are required to verify the inhibitory role of miR-195 in tumor angiogenesis and metastasis. Herein, we clarified the significance of miR-195 in tumor angiogenesis and metastasis of HCC by using in vitro assays, animal models and human specimens.