Deficiency of GFR alpha 1 promotes hepatocellular carcinoma progression but enhances oxaliplatin-mediated anti-tumor efficacy
Deficiency of GFR alpha 1 promotes hepatocellular carcinoma progression but enhances oxaliplatin-mediated anti-tumor efficacy
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GFR α 1 缺乏促进肝细胞癌进展，但增强奥沙利铂介导的抗肿瘤功效
DOI：
10.1016/j.phrs.2021.105815
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发表时间：
2021
影响因子：
9.3
通讯作者：
Liu Qiuyan
中科院分区：
文献类型：
--
作者：
Zhu Ha;Huang Mingyan;Luo Jianhua;Ji Xinpei;Liu Qiuyan
神经营养因子及其受体已被确定促进肿瘤进展。GFRα1是神经胶质细胞系来源的神经营养因子（GDNF）的受体，已被证明在成人肝组织中主要表达。我们的初步数据显示，GFRα1在肝细胞癌（HCC）组织中与匹配的非肿瘤组织相比显著下调。然而，GFRα1在HCC进展中的作用尚不清楚。本研究发现GFRα1在HCC组织中的表达与HCC患者预后较差呈负相关。沉默GFRα1表达可显著促进肝癌细胞生长和肿瘤转移，缩短肝癌荷瘤小鼠的生存期。肝癌细胞中强制表达GFRα1可显著逆转GFRα1沉默的促瘤作用，aav8介导的GFRα1转染肝癌肿瘤组织可显著抑制肿瘤生长，延长肝癌荷瘤小鼠的生存期。这些结果在GFRα1敲除小鼠模型中也得到了验证，den诱导的HCC癌变增加。机制上，GFRα1通过上调Claudin-1和ZO-1的表达抑制肝癌细胞上皮间质转化（EMT）。值得注意的是，沉默GFRα1表达可促进奥沙利铂介导的HCC细胞凋亡，延长肝癌小鼠的生存期，强制表达GFRα1可显著增加HCC细胞对奥沙利铂的耐药性。这些结果表明，缺乏GFRα1可促进HCC进展，但可增强化疗抗肿瘤疗效，提示GFRα1可能是HCC预后的候选生物标志物和潜在的治疗靶点。
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 verifiedin vivoin 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.