诺比列汀通过下调miR-15-5p使WNT/β-连环蛋白信号失活来抑制非小细胞肺癌。

Nobiletin Inhibits Non-Small-Cell Lung Cancer by Inactivating WNT/-Catenin Signaling through Downregulating miR-15-5p.

作者信息

Han Sang Hyup, Han Jeong Hee, Chun Wan Joo, Lee Sang Soo, Kim Hae Sung, Lee Jin Won

机构信息

Department of Surgery, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon 24253, Gangwon-Do, Republic of Korea.

Department of Pharmacology, College of Medicine, The Kangwon University of Korea, Chuncheon, Republic of Korea.

出版信息

Evid Based Complement Alternat Med. 2021 Dec 30;2021:7782963. doi: 10.1155/2021/7782963. eCollection 2021.

BACKGROUND

Nobiletin is a natural compound with anticancer activity; however, the mechanism is not clear.

METHODS

The inhibitory effect of nobiletin on non-small-cell lung cancer (NSCLC) cells was examined using soft agar, Transwell, and apoptosis analyses. Cancer stemness was measured by sphere assay. Genes and miRNAs regulated by nobiletin were identified by whole-genome sequencing. Protein levels were detected by western blot and immunofluorescence assays.

RESULTS

Nobiletin significantly inhibited NSCLC cell colony formation and sphere formation and induced apoptosis. Nobiletin upregulated negative regulators of WNT/-catenin signaling, including NKD1, AXIN2, and WIF1, while it inhibited the expression of -catenin and its downstream genes, including c-Myc, c-Jun, and cyclin D1. Furthermore, we identified that GN inhibits miR-15-5p expression in NSCLC cells and that NKD1, AXIN2, and WIF1 are the target genes of miR-15-5p.

CONCLUSIONS

Nobiletin has a strong inhibitory effect on NSCLC, and nobiletin plays an anticancer role by inhibiting miR-15-5p/-catenin signaling in NSCLC.

背景

川陈皮素是一种具有抗癌活性的天然化合物；然而，其作用机制尚不清楚。

方法

采用软琼脂法、Transwell法和凋亡分析检测川陈皮素对非小细胞肺癌（NSCLC）细胞的抑制作用。通过球体形成实验检测癌症干性。通过全基因组测序鉴定受川陈皮素调控的基因和微小RNA（miRNA）。采用蛋白质印迹法和免疫荧光法检测蛋白质水平。

结果

川陈皮素显著抑制NSCLC细胞集落形成和球体形成并诱导凋亡。川陈皮素上调WNT/β-连环蛋白信号通路的负调控因子，包括NKD1、AXIN2和WIF1，同时抑制β-连环蛋白及其下游基因（包括c-Myc、c-Jun和细胞周期蛋白D1）的表达。此外，我们发现川陈皮素抑制NSCLC细胞中miR-15-5p的表达，且NKD1、AXIN2和WIF1是miR-15-5p的靶基因。