Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma.
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Date
2016-05-24ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Humans
Carcinoma, Hepatocellular
Liver Neoplasms
Proto-Oncogene Proteins
MicroRNAs
Oligonucleotide Array Sequence Analysis
Apoptosis
Gene Expression Regulation, Neoplastic
RNA Interference
Mutation
Female
Male
Tumor Suppressor Protein p53
Apoptosis Regulatory Proteins
Hep G2 Cells
Research team
Signal Transduction & Molecular Pharmacology
Language
eng
Date accepted
2016-04-10
License start date
2016-05
Citation
Oncotarget, 2016, 7 (21), pp. 31361 - 31371
Publisher
IMPACT JOURNALS LLC