Inactivation of Stat3 and crosstalk of miRNA155-5p and FOXO3a contribute to the induction of IGFBP1 expression by beta-elemene in human lung cancer.
Inactivation of Stat3 and crosstalk of miRNA155-5p and FOXO3a contribute to the induction of IGFBP1 expression by beta-elemene in human lung cancer.
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DOI：
10.1038/s12276-018-0146-6
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发表时间：
2018-09-12
影响因子：
12.8
通讯作者：
Hann SS
中科院分区：
文献类型：
--
作者：
Zheng F;Tang Q;Zheng XH;Wu J;Huang H;Zhang H;Hann SS
β-榄香烯是天然植物的活性成分，已被证明具有抗癌特性。然而，这些影响的详细机制尚未确定。在这项研究中，我们证明β-榄香烯可以抑制肺癌细胞的生长。从机制上讲，我们发现β-榄香烯降低了信号转导子和转录激活子3（Stat3）和miRNA155-5p mRNA的磷酸化，但诱导了人叉头盒O类（FOXO）3a的蛋白表达；后两者在 Stat3 过表达的细胞中被消除。值得注意的是，miRNA155-5p 模拟物降低了 3-UTR 区域中 FOXO3a 荧光素酶报告基因的活性和蛋白质表达，而过表达的 FOXO3a 则抵消了 β-榄香烯对 miRNA155-5p 水平的降低。此外，β-榄香烯增加了胰岛素样生长因子结合蛋白1（IGFBP1）的mRNA和蛋白表达水平以及启动子活性；在具有沉默 FOXO3a 基因和 miRNA155-5p 模拟物的细胞中未观察到这一发现。最后，IGFBP1 的沉默阻断了 β-榄香烯抑制的细胞生长。在体内观察到类似的结果。总之，我们的结果表明，β-榄香烯通过 Stat3 失活以及 miRNA155-5p 和 FOXO3a 之间的相互作用来增加 IGFBP1 基因表达。这种作用会抑制人类肺癌细胞的生长。这些发现揭示了β-榄香烯对肺癌细胞抑制作用的新分子机制。在一种中草药中发现的一种化合物通过间接激活具有抗增殖特性的蛋白质来抑制肺癌细胞的生长。 Hann 及其来自中国广州中医药大学的同事发现了β-榄香烯（一种从温郁金植物中分离出来的天然化合物）介导抗癌作用的分子途径。他们表明，β-榄香烯使两种重要的调节分子（一种蛋白质和另一种小RNA）失活，同时还诱导一种促进杀死癌细胞的蛋白质的表达。这些变化导致防止细胞侵袭和扩散的蛋白质水平升高。总的来说，在细胞培养和小鼠模型中，肺癌细胞内部信号传导的改变导致生长减少。这些发现有助于解释为什么β-榄香烯具有作为肺癌治疗剂的潜力。
β-Elemene, an active component of natural plants, has been shown to exhibit anticancer properties. However, the detailed mechanism underlying these effects has yet to be determined. In this study, we show that β-elemene inhibits the growth of lung cancer cells. Mechanistically, we found that β-elemene decreased the phosphorylation of signal transducer and activator of transcription 3 (Stat3) and miRNA155-5p mRNA but induced the protein expression of human forkhead box class O (FOXO)3a; the latter two were abrogated in cells with overexpressed Stat3. Notably, miRNA155-5p mimics reduced FOXO3a luciferase reporter activity in the 3-UTR region and protein expression, whereas overexpressed FOXO3a countered the reduction of the miRNA155-5p levels by β-elemene. Moreover, β-elemene increased the mRNA and protein expression levels as well as promoter activity of insulin-like growth factor-binding protein 1 (IGFBP1); this finding was not observed in cells with a silenced FOXO3a gene and miRNA155-5p mimics. Finally, silencing of IGFBP1 blocked β-elemene-inhibited cell growth. Similar findings were observed in vivo. In summary, our results indicate that β-elemene increases IGFBP1 gene expression via inactivation of Stat3 followed by a reciprocal interaction between miRNA155-5p and FOXO3a. This effect leads to inhibition of human lung cancer cell growth. These findings reveal a novel molecular mechanism underlying the inhibitory effects of β-elemene on lung cancer cells. A compound found in one Chinese medicinal herb inhibits the growth of lung cancer cells by indirectly activating a protein with anti-proliferative properties. Hann and colleagues from the Guangzhou University of Chinese Medicine, China, uncovered the molecular pathways by which β-elemene, a natural compound isolated from the Curcuma wenyujin plant, mediates the anti-cancer effects. They showed that β-elemene inactivates the two important regulatory molecules, one protein and another small RNA, while also inducing the expression of one protein that promotes in killing cancer cells. These changes lead to elevated levels of the protein that prevents cell invasion and spread. Collectively, this altered signaling inside the lung cancer cell lead to reduced growth, in both cell-based culture and mouse model. The findings help explain why β-elemene has potential as a therapeutic agent in lung cancer.
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影响因子：
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