Deficiency of GFRα1 promotes hepatocellular carcinoma progression but enhances oxaliplatin-mediated anti-tumor efficacy.

Neurotrophic factors and their receptors have been identified to promote tumor progression. GFRα1, the receptor for glial cell line-derived neurotrophic factor (GDNF), has been demonstrated to be predominantly expressed in adult liver tissue. Our preliminary data showed that GFRα1 is significantly downregulated in hepatocellular carcinoma (HCC) tissue, compared to the matched non-neoplastic tissue. However, the role of GFRα1 in HCC progression remains unknown. Here we found that the expression of GFRα1 in HCC tissue is inversely correlated with the poorer prognosis of HCC patients. Silencing of GFRα1 expression markedly enhances HCC cell growth, tumor metastasis, as well as shortens the survival of HCC tumor-bearing mice. Forced expression of GFRα1 in HCC cells significantly reverses the tumor-promoting effects of GFRα1 silencing, and AAV8-mediated GFRα1 transfection in HCC tumor tissues significantly impedes tumor growth and prolongs the survival of HCC tumor-bearing mice. These results are also verified in vivo in GFRα1 knock-out mice model, with increased DEN-induced HCC carcinogenesis. Mechanistically, GFRα1 could inhibit epithelial-to-mesenchymal transition (EMT) of HCC cells, by upregulating expression of Claudin-1 and ZO-1. Of note, silencing of GFRα1 expression promotes oxaliplatin-mediated HCC cell apoptosis resulting in prolonged survival of HCC-bearing mice, and forced expression of GFRα1 markedly increased oxaliplatin resistance of HCC cells. These results demonstrate that deficiency of GFRα1 promotes HCC progression but enhances chemotherapeutic anti-tumor efficacy, suggesting that GFRα1 may be a candidate prognostic biomarker and a potential therapeutic target in HCC.