Zhang Zhixin, Liang Lili, Cao Gang
Department of Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Surgery, Shanxi Provincial Traditional Chinese Medicine Institute, Taiyuan, China.
J Biochem Mol Toxicol. 2021 Apr;35(4):e22721. doi: 10.1002/jbt.22721. Epub 2021 Feb 3.
Gastric cancer (GC) represents the fifth most human malignant disease and the third-most common cause of cancer-related death. Gambogic acid (GA) is a natural compound with a polyprenylated xanthone structure and possesses remarkable antitumor activity in a variety of cancer cells. However, the mechanism underlying the inhibitory effect of GA in GC is far from being completely understood. The goal of the present study is to investigate whether potential microRNAs are involved in antitumor effect of GA toward GC and to elucidate the possible mechanisms. We identified that miR-26a-5p was significantly increased by GA in GC cell lines and xenograft tumor. Downregulation of miR-26a-5p not only prevented GA-induced inhibition on GC cell growth, but also suppressed GA-induced apoptosis of GC cells. Informatics assay predicted that Wnt5a was regulated by miR-26a-5p and GA-induced downregulation of Wnt5a was prevented by anti-miR-26a-5p. Reporter gene assay showed that miR-26a-5p could negatively regulate Wnt5a through direct binding with 3'-UTR messenger RNA of Wnt5a. Thus, upregulation of Wnt5a exhibited the same action tendency for GA-induced GC cell growth and apoptosis as observed by downregulation of miR-26a-5p. In conclusion, these results indicated that the inhibitory effect of GA on GC was mediated by the upregulation of miR-26a-5p and downregulation of Wnt5a. Our study provided new clues for the potential therapeutic effect of GA against GC and highlighted the importance of miR-26a-5p/Wnt5a pathway in the regulation of GC development.
胃癌（GC）是人类第五大常见恶性疾病，也是癌症相关死亡的第三大常见原因。藤黄酸（GA）是一种具有多异戊二烯基氧杂蒽酮结构的天然化合物，在多种癌细胞中具有显著的抗肿瘤活性。然而，GA对GC抑制作用的潜在机制远未完全明确。本研究的目的是探讨潜在的微小RNA是否参与GA对GC的抗肿瘤作用，并阐明其可能的机制。我们发现GA可使GC细胞系和异种移植瘤中miR-26a-5p显著上调。下调miR-26a-5p不仅可阻止GA诱导的GC细胞生长抑制，还可抑制GA诱导的GC细胞凋亡。信息学分析预测Wnt5a受miR-26a-5p调控，抗miR-26a-5p可阻止GA诱导的Wnt5a下调。报告基因分析表明，miR-26a-5p可通过与Wnt5a的3'-UTR信使RNA直接结合而负向调控Wnt5a。因此，上调Wnt5a对GA诱导的GC细胞生长和凋亡的作用趋势与下调miR-26a-5p时相同。总之，这些结果表明GA对GC的抑制作用是由miR-26a-5p上调和Wnt5a下调介导的。我们的研究为GA对GC的潜在治疗作用提供了新线索，并突出了miR-26a-5p/Wnt5a通路在GC发生发展调控中的重要性。
