003), tumor microsatellite formation (P = 0.009), and presence of capsular invasion (P = 0.003; Table 1). To further validate the relation between miR-370 levels and survival of HCC patients, a tissue microarray, which contained 50 paired HCC samples and adjacent cancer-free samples obtained from HCC patients with a median follow-up of 33.5 months (range, 2.0-72.0; standard deviation [SD]: 24.4), was used for in situ hybridization of miR-370. Kaplan-Meier’s analysis revealed that lower miR-370 levels were correlated with shorter overall survival (OS) in HCC patients (Fig. 7F). Previous studies have demonstrated reduced miR-370 levels in gastrointestinal

stromal tumors,[37] bladder cancer,[38] neuroblastoma selleck cells,[39] and oral squamous cell carcinoma.[15] However, the role of miR-370 in hepatocarcinogenesis remains elusive. GSK-3 activity The current study revealed that miR-370 expression was gradually reduced during the development of HCC in DEN-treated rats. This decrease in miR-370 was observed in all tested hepatoma cells and in most HCC tumor samples. Moreover, we also demonstrated the suppressive effects of miR-370 on the malignant phenotype of HCC cells both in vitro and in vivo by gain-of-function

and loss-of-function experiments. Low expression of miR-370 in HCCs was associated with an aggressive disease phenotype, including advanced tumor stage, larger tumor size, and Linifanib (ABT-869) the presence of venous invasion, microsatellite tumors, and capsular invasion. Importantly, HCC patients with lower levels of miR-370 had shorter OS. All these data suggest that miR-370 may play a crucial role in the carcinogenesis and progression of HCC and may represent a novel therapeutic target and prognostic marker for HCC. However, our findings seem to be in conflict with other studies that

have reported a tumor-promoting function for miR-370.[16-18] miRNAs primarily exert their effects by regulating multiple target mRNAs.[6] Known targets of miR-370 include mitogen-activated protein kinase kinase kinase 8,[12] Wingless-type MMTV integration site family, member 10B,[13] forkhead box M1,[14] insulin receptor substrate 1,[15] transforming growth factor beta receptor II,[16] forkhead box protein O1,[17] neurofibromin 1,[18] and Cpt1α.[19] Most of these targets are implicated in cancer pathogenesis, some as oncogenes and others as tumor suppressors. The opposing effects of miR-370 on tumors may thus be attributed to the different functional natures of their target genes in a given cell type or under specific circumstances,[16] making it a context-dependent effector. The RNA-binding protein, LIN28A, and its paralog, LIN28B, are oncoproteins that are involved in many aspects of malignancies.[23, 24, 26, 28-32] The results of the current study suggested that LIN28A was a bona-fide target of miR-370 and promoted the proliferation, migration, and invasion of HCC cells.