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熊果酸通过 Rasf1 激活 Hippo 通路抑制胃癌的肿瘤发生。

Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer.

机构信息

Department of Internal Medicine, Chonbuk National University Medical School, Jeonju 54907, Korea.

Department of Physiology, Chonbuk National University Medical School, Jeonju 54907, Korea.

出版信息

Int J Mol Sci. 2019 Sep 23;20(19):4709. doi: 10.3390/ijms20194709.

DOI:10.3390/ijms20194709
PMID:31547587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6801984/
Abstract

The Hippo pathway is often dysregulated in many carcinomas, which results in various stages of tumor progression. Ursolic acid (UA), a natural compound that exists in many herbal plants, is known to obstruct cancer progression and exerts anti-carcinogenic effect on a number of human cancers. In this study, we aimed to examine the biological mechanisms of action of UA through the Hippo pathway in gastric cancer cells. MTT assay showed a decreased viability of gastric cancer cells after treatment with UA. Following treatment with UA, colony numbers and the sizes of gastric cancer cells were significantly diminished and apoptosis was observed in SNU484 and SNU638 cells. The invasion and migration rates of gastric cancer cells were suppressed by UA in a dose-dependent manner. To further determine the gene expression patterns that are related to the effects of UA, a microarray analysis was performed. Gene ontology analysis revealed that several genes, such as the Hippo pathway upstream target gene, ras association domain family (), and its downstream target genes (MST1, MST2, and LATS1) were significantly upregulated by UA, while the expression of YAP1 gene, together with oncogenes (FOXM1, KRAS, and BATF), were significantly decreased. Similar to the gene expression profiling results, the protein levels of RASSF1, MST1, MST2, LATS1, and p-YAP were increased, whereas those of CTGF were decreased by UA in gastric cancer cells. The p-YAP expression induced in gastric cancer cells by UA was reversed with RASSF1 silencing. In addition, the protein levels in the Hippo pathway were increased in the UA-treated xenograft tumor tissues as compared with that in the control tumor tissues; thus, UA significantly inhibited the tumorigenesis of gastric cancer in vivo in xenograft animals. Collectively, UA diminishes the proliferation and metastasis of gastric cancer via the regulation of Hippo pathway through Rassf1, which suggests that UA can be used as a potential chemopreventive and therapeutic agent for gastric cancer.

摘要

Hippo 通路在许多癌中经常失调，导致肿瘤进展的各个阶段。熊果酸（UA）是一种天然化合物，存在于许多草药植物中，已知可阻止癌症进展，并对多种人类癌症具有抗癌作用。在这项研究中，我们旨在通过 Hippo 通路研究 UA 在胃癌细胞中的作用机制。MTT 检测表明，UA 处理后胃癌细胞的活力降低。用 UA 处理后，SNU484 和 SNU638 细胞的集落数量和细胞大小明显减少，并观察到细胞凋亡。UA 以剂量依赖性方式抑制胃癌细胞的侵袭和迁移。为了进一步确定与 UA 作用相关的基因表达模式，进行了微阵列分析。基因本体分析显示，UA 显著上调了几个基因，如 Hippo 通路上游靶基因 ras 相关结构域家族 ()，及其下游靶基因 (MST1、MST2 和 LATS1)，而 YAP1 基因的表达与癌基因 (FOXM1、KRAS 和 BATF) 一起显著降低。与基因表达谱分析结果相似，UA 增加了胃癌细胞中 RASSF1、MST1、MST2、LATS1 和 p-YAP 的蛋白水平，而降低了 CTGF 的蛋白水平。UA 在胃癌细胞中诱导的 p-YAP 表达被 RASSF1 沉默逆转。此外，与对照肿瘤组织相比，UA 处理的异种移植肿瘤组织中的 Hippo 通路蛋白水平增加，因此，UA 可显著抑制异种移植动物体内胃癌的肿瘤发生。总之，UA 通过 Rassf1 调节 Hippo 通路减少胃癌的增殖和转移，表明 UA 可作为预防和治疗胃癌的潜在化学预防剂和治疗剂。

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