PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation
PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation
复制标题
PROX1 通过增强 β-catenin 表达和核转位来促进肝细胞癌增殖和索拉非尼耐药。
作者：
Liu, Y.;Ye, X.;Xie, Y.
Wnt/β-连环蛋白途径的异常激活在肝细胞癌（HCC）中很常见，并导致HCC的发生和进展。这种异常激活可能是由Wnt/β-连环蛋白途径基因的体细胞突变和/或Wnt/β-连环蛋白途径的失调引起的。对后者的机制仍然知之甚少。Prospero-related homeobox 1（PROX 1）是人结直肠癌中Wnt/β-catenin通路的下游靶点，PROX 1表达升高促进恶性进展。然而，Wnt/β-连环蛋白通路不调节肝脏和HCC细胞中的PROX 1表达。在这里，我们报告，PROX 1促进肝癌细胞在体外增殖和肝癌异种移植小鼠的肿瘤生长。PROX 1和β-连环蛋白水平在肿瘤组织和培养的肝癌细胞中呈正相关。PROX 1可通过刺激β-catenin启动子上调β-catenin的转录，并增强HCC细胞中β-catenin的核转位，从而导致Wnt/β-catenin通路的激活。此外，我们发现PROX 1表达的增加使HCC细胞对索拉非尼治疗更具抗性，索拉非尼治疗是晚期HCC的标准治疗。总的来说，我们已经确定PROX 1是激活HCC中Wnt/β-连环蛋白通路的关键因子，其促进HCC增殖和索拉非尼耐药。
Aberrant activation of the Wnt/beta-catenin pathway is frequent in hepatocellular carcinoma (HCC) and contributes to HCC initiation and progression. This abnormal activation may result from somatic mutations in the genes of the Wnt/beta-catenin pathway and/or dysregulation of the Wnt/beta-catenin pathway. The mechanism for the latter remains poorly understood. Prospero-related homeobox 1 (PROX1) is a downstream target of the Wnt/beta-catenin pathway in human colorectal cancer and elevated PROX1 expression promotes malignant progression. However, the Wnt/beta-catenin pathway does not regulate PROX1 expression in the liver and HCC cells. Here we report that PROX1 promotes HCC cell proliferation in vitro and tumor growth in HCC xenograft mice. PROX1 and beta-catenin levels are positively correlated in tumor tissues as well as in cultured HCC cells. PROX1 can upregulate beta-catenin transcription by stimulating the beta-catenin promoter and enhance the nuclear translocation of beta-catenin in HCC cells, which leads to the activation of the Wnt/beta-catenin pathway. Moreover, we show that increase in PROX1 expression renders HCC cells more resistant to sorafenib treatment, which is the standard therapy for advanced HCC. Overall, we have pinpointed PROX1 as a critical factor activating the Wnt/beta-catenin pathway in HCC, which promotes HCC proliferation and sorafenib resistance.