1. MiR-30e-3p Influences Tumor Phenotype through MDM2/TP53 Axis and Predicts Sorafenib Resistance in Hepatocellular Carcinoma
- Author
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Fabio Piscaglia, Francesco Vasuri, Daniela Pollutri, Catia Giovannini, Manuela Ferracin, Luigi Bolondi, Laura Gramantieri, Sara Marinelli, Matteo Ravaioli, Massimo Negrini, Andrea Casadei-Gardini, Santina Quarta, Matteo Cescon, Sabrina De Carolis, Francesca Benevento, Martina Gagliardi, Elisa Callegari, Francesca Fornari, 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., 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., and Fornari F.
- Subjects
0301 basic medicine ,Cancer Research ,Antineoplastic Agent ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,Diethylnitrosamine ,Genes, Tumor Suppressor ,biology ,hepatocellular carcinoma, miR-30e-3p, biomarker, treatment outcome ,Liver Neoplasms ,MicroRNA ,Proto-Oncogene Proteins c-mdm2 ,Epithelial cell adhesion molecule ,Hep G2 Cells ,hepatocellular carcinoma ,Sorafenib ,Epithelial Cell Adhesion Molecule ,Phenotype ,Neoplasm Proteins ,Oncology ,Liver Neoplasm ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Neoplastic Stem Cells ,Heterografts ,biomarker ,Mdm2 ,Heterograft ,Carcinogen ,Human ,medicine.drug ,Carcinoma, Hepatocellular ,Down-Regulation ,Socio-culturale ,Hep G2 Cell ,Antineoplastic Agents ,Context (language use) ,Neoplasm Protein ,03 medical and health sciences ,Proliferating Cell Nuclear Antigen ,medicine ,Animals ,Humans ,PTEN ,Neoplasm Invasiveness ,Gene Silencing ,neoplasms ,Cell Proliferation ,Neoplasm Invasivene ,Binding Sites ,Animal ,business.industry ,Binding Site ,PTEN Phosphohydrolase ,miR-30e-3p ,HCCS ,Genes, p53 ,medicine.disease ,digestive system diseases ,Rats ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Tissue Array Analysis ,Mutation ,Carcinogens ,treatment outcome ,biology.protein ,Cancer research ,Rat ,Neoplastic Stem Cell ,Cohort Studie ,Tumor Suppressor Protein p53 ,Tissue Array Analysi ,business - 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.
- Published
- 2020
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