Hedgehog signalling mediates drug resistance through targeting TAP1 in hepatocellular carcinoma
Hedgehog signalling mediates drug resistance through targeting TAP1 in hepatocellular carcinoma
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Hedgehog 信号通过靶向 TAP1 在肝细胞癌中介导耐药性
DOI：
10.1111/jcmm.15090
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发表时间：
2020-02-28
影响因子：
5.3
通讯作者：
Wu, Jian
中科院分区：
文献类型：
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作者：
Zhou, Xiao-Tian;Ding, Jia;Wu, Jian
多药耐药性是晚期肝细胞癌（HCC）生存率较低的原因之一。我们先前的研究表明，刺猬信号传导与肝癌发生，转移和化学抗性有关。本研究旨在发现肝癌化学抗性的基础分子机制。 TAP1和GLI1/2基因表达均在分化较差的肝癌细胞和HCC标本中评估。 TAP1启动子序列中的潜在GLI结合位点通过分子测定验证。与相邻的肝组织相比，大约75％的HCC标本表现出刺猬Gli1转录因子的表达升高。在分化较差的肝癌细胞中，GLI1/2和TAP1蛋白水平均显着升高。 HuH-7-trans和Huh-7-DN都表现出比其天然HuH-7细胞的核型异常和差异基因表达谱。在RNAi方法或特定的GLI1/2抑制剂GANT61抑制GLI1或TAP1基因后，对索拉非尼，阿霉素和顺铂的敏感性得到了显着提高。进一步的实验证实，刺猬转录因子GLI1/2与TAP1启动子结合，表明TAP1是GLI1/2靶基因之一。总之，TAP1受刺猬信号的直接转录控制。靶向刺猬信号传导赋予了对难治性HCC治疗中耐药性的新颖见解。
Multidrug resistance is one of the reasons for low survival of advanced hepatocellular carcinoma (HCC). Our previous studies indicate that the hedgehog signalling is involved in hepatic carcinogenesis, metastasis and chemo-resistance. The present study aims to uncover molecular mechanisms underlying hepatoma chemo-resistance. TAP1 and GLI1/2 gene expression was assessed in both poorly differentiated hepatoma cells and HCC specimens. Potential GLI-binding site in the TAP1 promoter sequence was validated by molecular assays. Approximately 75% HCC specimens exhibited an elevated expression of hedgehog GLI1 transcription factor compared with adjacent liver tissue. Both GLI1/2 and TAP1 protein levels were significantly elevated in poorly differentiated hepatoma cells. Both Huh-7-trans and Huh-7-DN displayed more karyotypic abnormalities and differential gene expression profiles than their native Huh-7 cells. Sensitivity to Sorafenib, doxorubicin and cisplatin was remarkably improved after either GLI1 or TAP1 gene was inhibited by an RNAi approach or by a specific GLI1/2 inhibitor, GANT61. Further experiments confirmed that hedgehog transcription factor GLI1/2 binds to the TAP1 promoter, indicating that TAP1 is one of GLI1/2 target genes. In conclusion, TAP1 is under direct transcriptional control of the hedgehog signalling. Targeting hedgehog signalling confers a novel insight into alleviating drug resistance in the treatment of refractory HCC.