Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway.
Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway.
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甲状腺激素在肝癌细胞中的化学疗法耐药性和转移促进作用是通过抑制FOXO1和BIM途径介导的。
DOI：
10.1038/cddis.2016.227
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发表时间：
2016-08-04
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
肝细胞癌（HCC）是全球癌症相关死亡的第三大原因，全身化疗是晚期HCC患者的主要治疗策略。化疗后预后不良是由于复发耐药的普遍结果。最近的研究表明，除了对肿瘤细胞的细胞毒性作用外，化疗还可以诱导支持肿瘤生长和转移的其他级联反应。在本研究中，我们发现甲状腺激素（TH）是一种有效的激素介导细胞分化和代谢，当甲状腺激素受体（TR）表达的HCC细胞受到顺铂、阿霉素和肿瘤坏死因子相关凋亡诱导配体（TRAIL）等癌症治疗药物的攻击时，甲状腺激素（TH）作为一种抗凋亡因子。TH/TR信号通过负调控促凋亡蛋白Bim促进化疗耐药，导致阿霉素诱导的化疗耐药HCC细胞转移。在化疗药物刺激的肝癌细胞中，Bim的异位表达可消除TH/ tr引发的细胞凋亡抵抗和转移。另外，叉头盒蛋白O1 （FoxO1）直接反激活了Bim的表达，而FoxO1受TH/TR的负调控。TH/TR通过akt介导的磷酸化触发FoxO1转录下调和核排斥抑制FoxO1活性。异位表达构成活性的FoxO1突变体FoxO1- aaa，而不是FoxO1-wt，减弱了TH/TR对Bim的抑制作用。我们的研究结果共同表明，Bim的表达是由fox01介导的，并通过TH/TR间接下调，导致化疗耐药和阿霉素促进肝癌细胞转移。
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late-stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin-induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR-triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells.
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影响因子：
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作者：
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通讯作者：
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3.9
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通讯作者：
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影响因子：
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