Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib.
Cristina QuintavalleSravanth Kumar HindupurLuca QuagliataPierlorenzo PallanteCecilia NigroGerolama CondorelliJesper Bøje AndersenKatrin Elisabeth TagschererWilfried RothFrancesco BeguinotMarkus Hermann HeimCharlotte Kiu Yan NgSalvatore PiscuoglioMatthias Sebastian MatterPublished in: Cell death & disease (2017)
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 PEDhigh 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.
Keyphrases
- poor prognosis
- cell migration
- cell proliferation
- nuclear factor
- cardiovascular disease
- long non coding rna
- type diabetes
- toll like receptor
- squamous cell carcinoma
- emergency department
- cell death
- gene expression
- drug induced
- binding protein
- single cell
- cell cycle
- skeletal muscle
- electronic health record
- small molecule
- inflammatory response
- endothelial cells
- adipose tissue
- rna seq
- big data
- climate change
- human health
- high glucose