Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma.
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.
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Laura
L
Lupini
Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.|Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
Felice
F
Pepe
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
Manuela
M
Ferracin
Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.
Chiara
C
Braconi
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Elisa
E
Callegari
Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.|Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
Sara
S
Pagotto
Division of Experimental Oncology 2 CRO, Aviano, Italy.
Riccardo
R
Spizzo
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Barbara
B
Zagatti
Department of Medicine and Aging Science, G. d'Annunzio University, Chieti, Italy.
Paola
P
Lanuti
S.Orsola-Malpighi University Hospital, Bologna, Italy.
Francesca
F
Fornari
Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.
Reza
R
Ghasemi
Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.|Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
Renato
R
Mariani-Costantini
S.Orsola-Malpighi University Hospital, Bologna, Italy.
Luigi
L
Bolondi
S.Orsola-Malpighi University Hospital, Bologna, Italy.
Laura
L
Gramantieri
Department of Experimental Therapeutics, MD Anderson Medical Centre, Houston, TX, USA.
George A
GA
Calin
Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
Silvia
S
Sabbioni
Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.|Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
Rosa
R
Visone
Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.|Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
Angelo
A
Veronese
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Massimo
M
Negrini
D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C541010:MIRN145 microRNA, human; C548912:MIRN483 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
HCC; PUMA; TP53; hsa-miR-145-5p; hsa-miR-483-3p