Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma.
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ICR Authors
Authors
Lupini, L
Pepe, F
Ferracin, M
Braconi, C
Callegari, E
Pagotto, S
Spizzo, R
Zagatti, B
Lanuti, P
Fornari, F
Ghasemi, R
Mariani-Costantini, R
Bolondi, L
Gramantieri, L
Calin, GA
Sabbioni, S
Visone, R
Veronese, A
Negrini, M
Pepe, F
Ferracin, M
Braconi, C
Callegari, E
Pagotto, S
Spizzo, R
Zagatti, B
Lanuti, P
Fornari, F
Ghasemi, R
Mariani-Costantini, R
Bolondi, L
Gramantieri, L
Calin, GA
Sabbioni, S
Visone, R
Veronese, A
Negrini, M
Document Type
Journal Article
Date
2016-05-24
Date Accepted
2016-04-10
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.
Citation
Oncotarget, 2016, 7 (21), pp. 31361 - 31371
Source Title
Publisher
IMPACT JOURNALS LLC
ISSN
1949-2553
eISSN
1949-2553
Collections
Research Team
Signal Transduction & Molecular Pharmacology