Dataset Information

Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma.

ABSTRACT: The miR-145-5p, which induces TP53-dependent apoptosis, is down-regulated in several tumors, including hepatocellular carcinomas (HCCs), but some HCCs show physiological expression of this miR. Here we demonstrate that in HCC cells carrying wild-type TP53 the steady activation of the miR-145 signaling selects clones resistant to apoptosis via up-regulation of the oncogenic miR-483-3p. Expression of the miR-145-5p and of the miR-483-3p correlated negatively in non-neoplastic liver (n=41; ?=-0.342, P=0.028), but positively in HCCs (n=21; ?=0.791, P<0.0001), which we hypothesized to be due to impaired glucose metabolism in HCCs versus normal liver. In fact, when liver cancer cells were grown in low glucose, miR-145-5p lowered miR-483-3p expression, allowing apoptosis, whereas when cells were grown in high glucose the levels of miR-483-3p increased, reducing the apoptotic rate. This indicates that depending on glucose availability the miR-145-5p has double effects on the miR-483-3p, either inhibitory or stimulatory. Moreover, resistance to apoptosis in clones overexpressing both miR-145-5p and miR-483-3p was abrogated by silencing the miR-483-3p. Our data highlight a novel mechanism of resistance to apoptosis in liver cancer cells harbouring wild type TP53 and suggest a potential role of miR-145-5p and miR-483-3p as druggable targets in a subset of HCCs.

SUBMITTER: Lupini L

PROVIDER: S-EPMC5058762 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma.

Lupini Laura L Pepe Felice F Ferracin Manuela M Braconi Chiara C Callegari Elisa E Pagotto Sara S Spizzo Riccardo R Zagatti Barbara B Lanuti Paola P Fornari Francesca F Ghasemi Reza R Mariani-Costantini Renato R Bolondi Luigi L Gramantieri Laura L Calin George A GA Calin George A GA Sabbioni Silvia S Visone Rosa R Veronese Angelo A Negrini Massimo M

Oncotarget 20160501 21

The miR-145-5p, which induces TP53-dependent apoptosis, is down-regulated in several tumors, including hepatocellular carcinomas (HCCs), but some HCCs show physiological expression of this miR. Here we demonstrate that in HCC cells carrying wild-type TP53 the steady activation of the miR-145 signaling selects clones resistant to apoptosis via up-regulation of the oncogenic miR-483-3p. Expression of the miR-145-5p and of the miR-483-3p correlated negatively in non-neoplastic liver (n=41; ρ=-0.342 ...[more]

PMID: 27120784

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Project description:Novel biomarkers for personalizing anticoagulation remain undetermined. We aimed to investigate the association of plasma miRNAs with pharmacokinetic-pharmacodynamic (PK-PD) profiles of rivaroxaban. This is a multicenter, exploratory study of miRNAs in a Chinese population. Healthy volunteers and patients receiving rivaroxaban were enrolled in the study. The area under the plasma concentration-time curve from time 0-t h (AUC0-t) and anti-Xa activity at 3 h (AXA3h) were measured in healthy volunteers, and AXA3h was measured in patients. MiRNAs were detected by miRNA microarray in 26 healthy volunteers with 20 mg rivaroxaban, and quantitative reverse transcription polymerase chain reaction was used to exclude undetectable ones. MiR-320a-3p and miR-483-5p were then quantified in 65 healthy volunteers and 71 patients. MiRNA levels at 3 h were compared between high and low AXA3h or AUC0-t subjects and in matched patients with or without bleeding during follow-up. The miRNA targets were predicted by TargetScan, miRTarBase, and miRDB. Validated genes were included in GO enrichment and KEGG analyses. The protein-protein interaction network was established by STRING and visualized by Cytoscape. A total of 136 Chinese subjects completed the study. In healthy volunteers taking 15 mg rivaroxaban, the miR-320a level at 3 h was significantly positively correlated with AXA3h and AUC0-t (r = 0.359, p = 0.025; r = 0.370, p = 0.02, respectively). A positive correlation was also observed between miR-483 and AXA3h or AUC0-t (r = 0.372, p = 0.02; r = 0.523, p = 0.001, respectively). MiR-320a and miR-483 levels at 3 h in the higher AUC0-t group were significantly higher than those at 0 h. MiR-483 levels at 3 h may distinguish healthy volunteers with high or low AXA3h or AUC0-t. In the 10 mg fed subgroup, higher 3 h mir-483 levels were also observed compared with the control group. No significant differences were found in the comparisons among patients. Bioinformatic analysis showed that these miRNAs may play a regulatory role by targeting ABCG2, ITGB3, PTEN, MAPK1/3, etc. CONCLUSIONS: MiR-320a and miR-483 levels were found to be associated with PK and PD profiles of rivaroxaban in healthy Chinese subjects. Further studies are required to verify these findings and explore the mechanisms.

Dataset Information

Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma.

Publications

Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma.

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