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

نویسندگان

  • 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
چکیده

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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عنوان ژورنال:

دوره 7  شماره 

صفحات  -

تاریخ انتشار 2016