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  • Title: MiR-30e-3p Influences Tumor Phenotype through MDM2/TP53 Axis and Predicts Sorafenib Resistance in Hepatocellular Carcinoma.
    Author: Gramantieri L, Pollutri D, Gagliardi M, Giovannini C, Quarta S, Ferracin M, Casadei-Gardini A, Callegari E, De Carolis S, Marinelli S, Benevento F, Vasuri F, Ravaioli M, Cescon M, Piscaglia F, Negrini M, Bolondi L, Fornari F.
    Journal: Cancer Res; 2020 Apr 15; 80(8):1720-1734. PubMed ID: 32015093.
    Abstract:
    The molecular background of hepatocellular carcinoma (HCC) is highly heterogeneous, and biomarkers predicting response to treatments are an unmet clinical need. We investigated miR-30e-3p contribution to HCC phenotype and response to sorafenib, as well as the mutual modulation of TP53/MDM2 pathway, in HCC tissues and preclinical models. MiR-30e-3p was downregulated in human and rat HCCs, and its downregulation associated with TP53 mutations. TP53 contributed to miR-30e-3p biogenesis, and MDM2 was identified among its target genes, establishing an miR-30e-3p/TP53/MDM2 feedforward loop and accounting for miR-30e-3p dual role based on TP53 status. EpCAM, PTEN, and p27 were demonstrated as miR-30e-3p additional targets mediating its contribution to stemness and malignant features. In a preliminary cohort of patients with HCC treated with sorafenib, increased miR-30e-3p circulating levels predicted the development of resistance. In conclusion, molecular background dictates miR-30e-3p dual behavior in HCC. Mdm2 targeting plays a predominant tumor suppressor function in wild-type TP53 contexts, whereas other targets such as PTEN, p27, and EpCAM gain relevance and mediate miR-30e-3p oncogenic role in nonfunctional TP53 backgrounds. Increased circulating levels of miR-30e-3p predict the development of sorafenib resistance in a preliminary series of patients with HCC and deserve future investigations. SIGNIFICANCE: The dual role of miR-30e-3p in HCC clarifies how the molecular context dictates the tumor suppressor or oncogenic function played by miRNAs.
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