TY - JOUR
T1 - Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma
AU - Lupini, Laura
AU - Pepe, Felice
AU - Ferracin, Manuela
AU - Braconi, Chiara
AU - Callegari, Elisa
AU - Pagotto, Sara
AU - Spizzo, Riccardo
AU - Zagatti, Barbara
AU - Lanuti, Paola
AU - Fornari, Francesca
AU - Ghasemi, Reza
AU - Mariani-Costantini, Renato
AU - Bolondi, Luigi
AU - Gramantieri, Laura
AU - Calin, George A.
AU - Sabbioni, Silvia
AU - Visone, Rosa
AU - Veronese, Angelo
AU - Negrini, Massimo
PY - 2016/5/24
Y1 - 2016/5/24
N2 - 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.
AB - 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.
KW - HCC
KW - Hsa-miR-145-5p
KW - Hsa-miR-483-3p
KW - PUMA
KW - TP53
UR - http://www.scopus.com/inward/record.url?scp=84971578707&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84971578707&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.8913
DO - 10.18632/oncotarget.8913
M3 - Article
C2 - 27120784
AN - SCOPUS:84971578707
SN - 1949-2553
VL - 7
SP - 31361
EP - 31371
JO - Oncotarget
JF - Oncotarget
IS - 21
ER -