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 ofmiR-30e-3p inHCCclarifies how the molecular context dictates the tumor suppressor or oncogenic function played by miRNAs.

MiR-30e-3p influences tumor phenotype through MDM2/TP53 axis and predicts sorafenib resistance in hepatocellular carcinoma

Gramantieri L.;Pollutri D.;Gagliardi M.;Giovannini C.;Quarta S.;Ferracin M.;Callegari E.;De Carolis S.;Marinelli S.;Benevento F.;Vasuri F.;Ravaioli M.;Cescon M.;Piscaglia F.;Bolondi L.;Fornari F.
2020

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 ofmiR-30e-3p inHCCclarifies how the molecular context dictates the tumor suppressor or oncogenic function played by miRNAs.
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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/796808
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