Oncotarget

Research Papers:

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

Laura Lupini _, Felice Pepe, Manuela Ferracin, Chiara Braconi, Elisa Callegari, Sara Pagotto, Riccardo Spizzo, Barbara Zagatti, Paola Lanuti, Francesca Fornari, Reza Ghasemi, Renato Mariani-Costantini, Luigi Bolondi, Laura Gramantieri, George A. Calin, Silvia Sabbioni, Rosa Visone, Angelo Veronese, Massimo Negrini

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Oncotarget. 2016; 7:31361-31371. https://doi.org/10.18632/oncotarget.8913

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Abstract

Laura Lupini1,*, Felice Pepe2,8,*, Manuela Ferracin3, Chiara Braconi4, Elisa Callegari1, Sara Pagotto2,8, Riccardo Spizzo5, Barbara Zagatti1, Paola Lanuti6, Francesca Fornari7, Reza Ghasemi2, Renato Mariani-Costantini2,8, Luigi Bolondi7, Laura Gramantieri7, George A. Calin9, Silvia Sabbioni10, Rosa Visone2,8, Angelo Veronese2,8, Massimo Negrini1

1Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

2Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d’Annunzio University Foundation, Chieti, Italy

3Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

4Division of Cancer Therapeutics, Institute of Cancer Research, London, UK

5Division of Experimental Oncology 2 CRO, Aviano, Italy

6Department of Medicine and Aging Science, G. d’Annunzio University, Chieti, Italy

7S.Orsola-Malpighi University Hospital, Bologna, Italy

8Department of Medical, Oral and Biotechnological Sciences, G. d’Annunzio University, Chieti, Italy

9Department of Experimental Therapeutics, MD Anderson Medical Centre, Houston, TX, USA

10Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy

*These authors have contributed equally to this work

Correspondence to:

Angelo Veronese, email: a.veronese@unich.it

Massimo Negrini, email: ngm@unife.it

Keywords: TP53, hsa-miR-145-5p, hsa-miR-483-3p, HCC, PUMA

Received: October 15, 2015    Accepted: April 10, 2016    Published: April 22, 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.


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