Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α
Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α
复制标题
肝细胞癌索拉非尼耐药性的逆转：表观遗传调控 14-3-3 eta/缺氧诱导因子 1 α 的破坏
DOI：
10.1038/s41420-019-0200-8
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发表时间：
2019-07-19
影响因子：
7
通讯作者：
Li, Yuan
中科院分区：
文献类型：
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作者：
Qiu, Yongxin;Shan, Wenqi;Li, Yuan
索拉非尼耐药是晚期/复发性肝细胞癌（HCC）治疗的主要障碍之一。本研究以索拉非尼耐药HCC细胞和裸鼠异种移植为实验模型。一组接受索拉非尼治疗的晚期复发HCC患者被用于评估该治疗的临床意义。我们的数据显示14-3-3 eta在HCC中维持索拉非尼耐药。一项潜在的分子机制分析表明，14-3-3 eta通过抑制泛素依赖性蛋白酶体蛋白降解来稳定缺氧诱导因子1 α (HIF-1 α)，从而维持癌症干细胞（CSC）的特性。我们进一步发现microRNA-16 （miR-16）是一种有效的miRNA，通过靶向14-3-3 eta的3'-UTR逆转索拉非尼耐药，从而抑制14-3-3。/HIF-1 α /CSC性质。在HCC患者中，miR-16的表达与14-3-3 eta、HIF-1 α或CSC特性之间存在显著的负相关。进一步分析表明，miR-16低表达而14-3-3 eta高表达可预测索拉非尼耐药和生存不良。总之，我们目前的研究表明，miR-16/14-3-3 eta参与HCC索拉非尼耐药，这两个因素可能是预测索拉非尼治疗反应的潜在治疗靶点和生物标志物。
Sorafenib resistance is one of the main obstacles to the treatment of advanced/recurrent hepatocellular carcinoma (HCC). Here, sorafenib-resistant HCC cells and xenografts in nude mice were used as experimental models. A cohort of patients with advanced recurrent HCC who were receiving sorafenib therapy was used to assess the clinical significance of this therapy. Our data showed that 14-3-3 eta maintained sorafenib resistance in HCC. An analysis of the underlying molecular mechanisms revealed that 14-3-3 eta stabilizes hypoxia-inducible factor 1 alpha (HIF-1 alpha) through the inhibition of ubiquitin-dependent proteasome protein degradation, which leads to the maintenance of cancer stem cell (CSC) properties. We further found that microRNA-16 (miR-16) is a competent miRNA that reverses sorafenib resistance by targeting the 3'-UTR of 14-3-3 eta and thereby inhibits 14-3-3./HIF-1 alpha/CSC properties. In HCC patients, significant negative correlations were found between the expression of miR-16 and 14-3-3 eta, HIF-1 alpha, or CSC properties. Further analysis showed that low miR-16 expression but high 14-3-3 eta expression can prognosticate sorafenib resistance and poor survival. Collectively, our present study indicated that miR-16/14-3-3 eta is involved in sorafenib resistance in HCC and that these two factors could be potential therapeutic targets and biomarkers for predicting the response to sorafenib treatment.