Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis

Marta Anna Kowalik, Giulia Guzzo, Andrea Morandi, Andrea Perra, Silvia Menegon, Ionica Masgras, Elena Trevisan, Maria Maddalena Angioni, Francesca Fornari, Luca Quagliata, Giovanna Maria Ledda-Columbano, Laura Gramantieri, Luigi Terracciano, Silvia Giordano, Paola Chiarugi, Andrea Rasola, Amedeo Columbano

Research output: Contribution to journalArticlepeer-review

Abstract

Metabolic changes are associated with cancer, but whether they are just bystander effects of deregulated oncogenic signaling pathways or characterize early phases of tumorigenesis remains unclear. Here we show in a rat model of hepatocarcinogenesis that early preneoplastic foci and nodules that progress towards hepatocellular carcinoma (HCC) are characterized both by inhibition of oxidative phosphorylation (OXPHOS) and by enhanced glucose utilization to fuel the pentose phosphate pathway (PPP). These changes respectively require increased expression of the mitochondrial chaperone TRAP1 and of the transcription factor NRF2 that induces the expression of the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase (G6PD), following miR-1 inhibition. Such metabolic rewiring exclusively identifies a subset of aggressive cytokeratin-19 positive preneoplastic hepatocytes and not slowly growing lesions. No such metabolic changes were observed during non-neoplastic liver regeneration occurring after two/third partial hepatectomy. TRAP1 silencing inhibited the colony forming ability of HCC cells while NRF2 silencing decreased G6PD expression and concomitantly increased miR-1; conversely, transfection with miR-1 mimic abolished G6PD expression. Finally, in human HCC patients increased G6PD expression levels correlates with grading, metastasis and poor prognosis. Our results demonstrate that the metabolic deregulation orchestrated by TRAP1 and NRF2 is an early event restricted to the more aggressive preneoplastic lesions.

Original languageEnglish
Pages (from-to)32375-32393
Number of pages19
JournalOncotarget
Volume7
Issue number22
DOIs
Publication statusPublished - May 31 2016

Keywords

  • HCC
  • NRF2
  • Oxidative phosphorylation
  • Pentose phosphate pathway
  • TRAP1

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis'. Together they form a unique fingerprint.

Cite this