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. GFR alpha 1, 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 GFR alpha 1 is significantly downregulated in hepatocellular carcinoma (HCC) tissue, compared to the matched non-neoplastic tissue. However, the role of GFR alpha 1 in HCC progression remains unknown. Here we found that the expression of GFR alpha 1 in HCC tissue is inversely correlated with the poorer prognosis of HCC patients. Silencing of GFR alpha 1 expression markedly enhances HCC cell growth, tumor metastasis, as well as shortens the survival of HCC tumor-bearing mice. Forced expression of GFR alpha 1 in HCC cells significantly reverses the tumor-promoting effects of GFR alpha 1 silencing, and AAV8-mediated GFR alpha 1 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 GFR alpha 1 knock-out mice model, with increased DEN-induced HCC carcinogenesis. Mechanistically, GFR alpha 1 could inhibit epithelial-to-mesenchymal transition (EMT) of HCC cells, by upregulating expression of Claudin-1 and ZO-1. Of note, silencing of GFR alpha 1 expression promotes oxaliplatin-mediated HCC cell apoptosis resulting in prolonged survival of HCC-bearing mice, and forced expression of GFR alpha 1 markedly increased oxaliplatin resistance of HCC cells. These results demonstrate that deficiency of GFR alpha 1 promotes HCC progression but enhances chemotherapeutic anti-tumor efficacy, suggesting that GFR alpha 1 may be a candidate prognostic biomarker and a potential therapeutic target in HCC.