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., et al. (2020). MiR-30e-3p influences tumor phenotype through MDM2/TP53 axis and predicts sorafenib resistance in hepatocellular carcinoma. CANCER RESEARCH, 80(8), 1720-1734 [10.1158/0008-5472.CAN-19-0472].
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.;Ferracin M.;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.File | Dimensione | Formato | |
---|---|---|---|
benevento.pdf
Open Access dal 04/02/2021
Tipo:
Postprint
Licenza:
Licenza per accesso libero gratuito
Dimensione
7.76 MB
Formato
Adobe PDF
|
7.76 MB | Adobe PDF | Visualizza/Apri |
00085472can190472-sup-216842_4_supp_6039954_q4pgpn.doc
accesso aperto
Tipo:
File Supplementare
Licenza:
Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY)
Dimensione
130.5 kB
Formato
Microsoft Word
|
130.5 kB | Microsoft Word | Visualizza/Apri |
00085472can190472-sup-216842_4_supp_6039958_q4ny44.doc
accesso aperto
Tipo:
File Supplementare
Licenza:
Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY)
Dimensione
28.77 MB
Formato
Microsoft Word
|
28.77 MB | Microsoft Word | Visualizza/Apri |
00085472can190472-sup-216842_4_supp_6040014_q4khxv.doc
accesso aperto
Tipo:
File Supplementare
Licenza:
Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY)
Dimensione
142.5 kB
Formato
Microsoft Word
|
142.5 kB | Microsoft Word | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.