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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)31361-31371
Number of pages11
JournalOncotarget
Volume7
Issue number21
DOIs
Publication statusPublished - May 24 2016

Keywords

  • HCC
  • Hsa-miR-145-5p
  • Hsa-miR-483-3p
  • PUMA
  • TP53

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma'. Together they form a unique fingerprint.

  • Cite this

    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, G. A., Sabbioni, S., Visone, R., Veronese, A., & Negrini, M. (2016). Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma. Oncotarget, 7(21), 31361-31371. https://doi.org/10.18632/oncotarget.8913