a b s t r a c t microRNAs aberrant behavior in heptocellular carcinoma (HCC) plays a major role in HCC pathogenesis. miR-615-5p expression has never been evaluated in HCC. We showed that miR-615-5p was preferentially expressed in HCC, cirrhotic liver tissues and HCC cell lines, but undetected in normal livers. Forced miR-615-5p expression in HCC cell lines led to significant decrease in cell growth and migration. In-silico predication revealed insulin-like growth factor-II (IGF-II) as a potential downstream target for miR-615-5p. Forcing the expression of miR-615-5p showed downregulation of IGF-II mRNA, as well as inhibition of the luciferase activity in a luciferase reporter vector harboring the IGF-II-3 0 UTR target sequence. miR-615-5p acts as tumor-suppressor in HCC through targeting IGF-II.

This study aimed to identify a single miRNA or miR (microRNA) which regulates the three insulin‐like growth factor‐2‐mRNA‐binding proteins (IGF2BP1, 2 and 3). Bioinformatics predicted miR‐1275 to simultaneously target the three IGF2BPs, and screening revealed miR‐1275 to be underexpressed in hepatocellular carcinoma (HCC) tissues. Transfection of HuH‐7 cells with miR‐1275 suppressed IGF2BPs expression and all three IGF2BPs were confirmed as targets of miR‐1275. Ectopic expression of miR‐1275 and knockdown of IGF2BPs inhibited malignant cell behaviors, and also reduced IGF1R protein and mRNA. Finally IGF1R was validated as a direct target of miR‐1275. These findings indicate that the tumor‐suppressor miR‐1275 can control HCC tumor growth partially through simultaneously regulating the oncogenic IGF2BPs and IGF1R.

Summary To study the feasibility of endovascular management of early hepatic artery thrombosis (HAT) after living‐donor liver transplantation (LDLT) and to clarify its role as a less invasive alternative to open surgery. A retrospective review of 360 recipients who underwent LDLT. Early HAT developed in 13 cases (3.6%). Diagnosis was performed using Doppler, CT angiography, and digital subtraction angiography. Intra‐arterial thrombolysis (IAT) was performed using streptokinase or tPA. In case of underlying stricture, PTA was attempted. If the artery did not recanalize, continuous infusion was performed and monitored using Doppler US. Initial surgical revascularization was successful in 2/13 cases. IAT was performed in 11/13 cases. The initial success rate was 81.8% (9/11), the failure rate was 18.2% (2/11). Rebound thrombosis developed in 33.3% (3/9). Hemorrhage developed after IAT in 2/11 cases (18.2%). Definite endovascular treatment of HAT was achieved in 6/11 cases (54.5%) and definite treatment (surgical, endovascular or combined) in 9/13 cases (69%). (Follow‐up 4 months–4 years). Endovascular management of early HAT after LDLT is a feasible and reliable alternative to open surgery. It plays a role as a less invasive approach with definite endovascular treatment rate of 54.5%.

IGF2BP 1, 2 and 3 control the fate of many transcripts. Immunoprecipitation studies demonstrated the IGF2BPs to bind to IGF1R mRNA, and our laboratory has recently shown them to post-transcriptionally regulate IGF1R. This study sought to identify a microRNA regulating the IGF2BPs and consequently IGF1R. All three IGF2BPs were among the top-ranked predicted targets of let-7i. Let-7i was downregulated in HCC tissues, and transfection of HuH-7 with let-7i inhibited malignant cell behaviors and decreased IGF2BPs transcripts. Direct binding of let-7i to IGF2BP2 and IGF2BP3 3'UTRs was confirmed, and the effect of let-7i caused a decrease in the IGF2BPs' target gene, the IGF1R. IGF1R mRNA was inversely correlated with let-7i in HCC tissues and was reduced upon let-7i transfection into HuH-7. Reporter assays validated IGF1R as a target of let-7i. Therefore, let-7i may control HCC tumorigenesis by regulating IGF1R directly and indirectly by interrupting the interplay between IGF1R and the IGF2BPs.

Abstract. MicroRNAs (miRs) have a major role in the pathogenesis of hepatocellular carcinoma (HCC). As the insulin-like growth factor (IGF) axis is a highly tumorigenic pathway in HCC, the present study attempted to target it with miRs. Potential targeting of crucial members of the IGF axis by miRNAs at the 3'-untranslated region (3'-UTR) was predicted using bioinformatic tools, such as microrna.org, Diana lab and Targetscan, while 5'-UTR targeting was predicted using bibiserv software. Expression profiling of obtained miRNAs was performed using quantitative polymerase chain reaction (qPCR) in 22 non-metastatic HCC biopsy samples and 10 healthy tissues. To investigate the impact of miRNAs on their potential downstream targets, transfection of miRNAs was performed in HuH-7 cells and the targets' expression was quantified using qPCR. Transcripts of insulin-like growth factor-1 receptor (IGF-1R), insulin-like growth factor binding protein-3 (IGFBP-3) and IGF-II were found to be potentially targeted at the 5'-UTR and 3'-UTR regions by the single clustered hepatic metastamiRs miR-96-5p and miR-182-5p. The two miRNAs showed a similar expression pattern in HCC tissues compared to those in healthy tissues. Forced expression of miR-96-5p and miR-182-5p in the HCC cell line HuH-7 had inducing effects on IGFBP-3 and IGF-II transcripts. Of note, the two miRs had differential effects on IGF-1R, where miR-96-5p induced IGF-1R mRNA expression and miR-182-5p inhibited its expression. The present study revealed the pleiotropic impact of the single clustered hepatic metastamiRs miR-96-5p and miR-182-5p on IGF-1R, and an inducing effect on IGF-II and IGFBP-3 in hepatocellular carcinoma.