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, P=0.028), but positively in HCCs (n=21; ρ=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.

Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma / Lupini, Laura; Pepe, Felice; Ferracin, Manuela; Braconi, Chiara; Callegari, Elisa; Pagotto, Sara; Spizzo, Riccardo; Zagatti, Barbara; Lanuti, Paola; Fornari, Francesca; Ghasemi, Reza; Mariani-Costantini, Renato; Bolondi, Luigi; Gramantieri, Laura; Calin, George A.; Sabbioni, Silvia; Visone, Rosa; Veronese, Angelo; Negrini, Massimo. - In: ONCOTARGET. - ISSN 1949-2553. - ELETTRONICO. - 7:21(2016), pp. 31361-31371. [10.18632/oncotarget.8913]

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

FERRACIN, MANUELA;FORNARI, FRANCESCA;BOLONDI, LUIGI;GRAMANTIERI, LAURA;
2016

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; ρ=-0.342, P=0.028), but positively in HCCs (n=21; ρ=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.
2016
Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma / Lupini, Laura; Pepe, Felice; Ferracin, Manuela; Braconi, Chiara; Callegari, Elisa; Pagotto, Sara; Spizzo, Riccardo; Zagatti, Barbara; Lanuti, Paola; Fornari, Francesca; Ghasemi, Reza; Mariani-Costantini, Renato; Bolondi, Luigi; Gramantieri, Laura; Calin, George A.; Sabbioni, Silvia; Visone, Rosa; Veronese, Angelo; Negrini, Massimo. - In: ONCOTARGET. - ISSN 1949-2553. - ELETTRONICO. - 7:21(2016), pp. 31361-31371. [10.18632/oncotarget.8913]
Lupini, Laura; Pepe, Felice; Ferracin, Manuela; Braconi, Chiara; Callegari, Elisa; Pagotto, Sara; Spizzo, Riccardo; Zagatti, Barbara; Lanuti, Paola; Fornari, Francesca; Ghasemi, Reza; Mariani-Costantini, Renato; Bolondi, Luigi; Gramantieri, Laura; Calin, George A.; Sabbioni, Silvia; Visone, Rosa; Veronese, Angelo; Negrini, Massimo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/564546
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