Cinnamaldehyde induces cell apoptosis mediated by a novel circular RNA hsa_circ_0043256 in non-small cell lung cancer

• Published in: Biochemical and biophysical research communications 2017-11, Vol.493 (3), p.1260-1266
• Main Authors: Tian, Fang, Yu, C.T., Ye, W.D., Wang, Qian
• Format: Article
• Language: English
• Subjects: Acrolein - analogs & derivatives; Acrolein - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; beta Catenin - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cinnamaldehyde; Gene Expression Regulation, Neoplastic - drug effects; hsa_circ_0043256; Humans; ITCH; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Mice, Inbred BALB C; MicroRNAs - genetics; NSCLC; Repressor Proteins - genetics; RNA - genetics; Ubiquitin-Protein Ligases - genetics; Wnt Proteins - drug effects; Wnt Proteins - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.09.136

Cinnamaldehyde (CA), the primary chemical component of the Chinese traditional herb Cinnamomum cassia, is an effective cytotoxic agent against various human cancers. Our previous study indicated that CA could trigger apoptosis in three kinds of non-small cell lung cancer (NSCLC) cells. However, CA mechanism of action in NSCLC has not been unveiled completely. Herein, we showed that a novel circular RNA hsa_circ_0043256 was upregulated in NSCLC cells in response to CA treatment, as detected by microarray and real-time PCR. Hsa_circ_0043256 could inhibit cell proliferation and induce apoptosis, while hsa_circ_0043256 knock-down could promote cell proliferation and restrain apoptosis induced by CA. Bioinformatics analysis predicted that hsa_circ_0043256 could work as a miR-1252 sponge, which could in turn directly target a vital negative regulator of Canonical Wnt signaling, Itchy E3 ubiquitin protein ligase (ITCH), as validated by dual-luciferase assay. Western blot results further confirmed that hsa_circ_0043256 could upregulate ITCH expression, whereas miR-1252 could partially abolish this effect. Interestingly, hsa_circ_0043256 knock-down could weaken Wnt/β-catenin pathway inhibition induced by CA. Finally, we discovered that CA induced apoptosis and meanwhile upregulated hsa_circ_0043256 expression in vivo. Immunohistochemical analysis revealed that ITCH expression was positively association with hsa_circ_0043256 levels. Above all, we characterized a new mechanism mediated by hsa_circ_0043256/miR-1252/ITCH axis in CA function against NSCLC, providing a novel insight into lung cancer therapy. •We firstly explored circular RNA function involved in mechanism of cinnamaldehyde against non-small cell lung cancer.•Circular RNA has_circ_0043256 inhibited cell proliferation and induced apoptosis in NCI-H460 and A549 cells.•Has_circ_0043256 was for the first time reported as a cinnamaldehyde-responsive circRNA in vitro and in vivo.•Has_circ_0043256 acted as endogenous sponge of miR-1252, relieving its target ITCH, and regulated Wnt/β-catenin pathway.