Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer
Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer
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DOI：
10.3390/ijms20194709
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发表时间：
2019-10-01
影响因子：
5.6
通讯作者：
Kim, Soo Mi
中科院分区：
文献类型：
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作者：
Kim, Seong-Hun;Jin, Hua;Kim, Soo Mi
Hippo通路在许多癌症中经常失调，从而导致肿瘤进展的不同阶段。熊果酸（UA）是一种存在于许多草本植物中的天然化合物，已知可以阻止癌症的进展并对许多人类癌症具有抗癌作用。在本研究中，我们旨在研究UA在胃癌细胞中通过Hippo通路作用的生物学机制。MTT试验显示UA治疗后胃癌细胞活力下降。经UA处理后，胃癌细胞的集落数量和大小明显减少，并在SNU484和SNU638细胞中观察到凋亡。UA对胃癌细胞的侵袭和迁移速率具有剂量依赖性。为了进一步确定与UA效应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Hippo通路上游靶基因、ras关联结构域家族（RASSF1）及其下游靶基因（MST1、MST2、LATS1），显著下调YAP1基因及致癌基因（FOXM1、KRAS、BATF）的表达。与基因表达谱分析结果相似，UA使胃癌细胞中RASSF1、MST1、MST2、LATS1和p-YAP蛋白水平升高，而CTGF蛋白水平降低。RASSF1沉默后，UA诱导的胃癌细胞p-YAP表达逆转。此外，与对照肿瘤组织相比，ua处理的异种移植肿瘤组织中Hippo通路蛋白水平升高；由此可见，UA显著抑制异种移植动物体内胃癌的发生。综上所述，UA可通过Rassf1调控Hippo通路，从而抑制胃癌的增殖和转移，这表明UA可作为一种潜在的胃癌化学防治药物。
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 (RASSF1), 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.