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Inactivation of Stat3 and crosstalk of miRNA155-5p and FOXO3a contribute to the induction of IGFBP1 expression by beta-elemene in human lung cancer

F. Zheng,Qing Tang,Xiaoxiao Zheng,Jing-jing Wu,Haiding Huang,Haibo Zhang,S. Hann

Published 2018 in Experimental and Molecular Medicine

ABSTRACT

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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