Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib

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  • Cristina Quintavalle
  • Sravanth Kumar Hindupur
  • Luca Quagliata
  • Pierlorenzo Pallante
  • Cecilia Nigro
  • Gerolama Condorelli
  • Andersen, Jesper Bøje
  • Katrin Elisabeth Tagscherer
  • Wilfried Roth
  • Francesco Beguinot
  • Markus Hermann Heim
  • Charlotte Kiu Yan Ng
  • Salvatore Piscuoglio
  • Matthias Sebastian Matter

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death with limited treatment options and frequent resistance to sorafenib, the only drug currently approved for first-line therapy. Therefore, better understanding of HCC tumor biology and its resistance to treatment is urgently needed. Here, we analyzed the role of phosphoprotein enriched in diabetes (PED) in HCC. PED has been shown to regulate cell proliferation, apoptosis and migration in several types of cancer. However, its function in HCC has not been addressed yet. Our study revealed that both transcript and protein levels of PED were significantly high in HCC compared with non-tumoral tissue. Clinico-pathological correlation revealed that PED(high) HCCs showed an enrichment of gene signatures associated with metastasis and poor prognosis. Further, we observed that PED overexpression elevated the migration potential and PED silencing the decreased migration potential in liver cancer cell lines without effecting cell proliferation. Interestingly, we found that PED expression was regulated by a hepatocyte specific nuclear factor, HNF4α. A reduction of HNF4α induced an increase in PED expression and consequently, promoted cell migration in vitro. Finally, PED reduced the antitumoral effect of sorafenib by inhibiting caspase-3/7 activity. In conclusion, our data suggest that PED has a prominent role in HCC biology. It acts particularly on promoting cell migration and confers resistance to sorafenib treatment. PED may be a novel target for HCC therapy and serve as a predictive marker for treatment response against sorafenib.

Original languageEnglish
Article numbere3138
JournalCell Death & Disease
Issue number10
Number of pages9
Publication statusPublished - 26 Oct 2017

    Research areas

  • Journal Article

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