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 (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.
Highlights
Gastric carcinoma is one of the most deadly cancers and it is associated with a high mortality rate [1,2,3,4]
Gene ontology analysis revealed that several genes, including the upstream regulator of the Hippo signaling pathway (MST1, MST2, LATS1) and ras association domain family (RASSF1), were significantly upregulated and its downstream target genes of Hippo signaling pathway (YAP1, CTFG, FOXM1, KRAS, BATF) were significantly downregulated by Ursolic acid (UA) treatment
In agreement with the gene expression profiling study, we found that UA increased the expression of the Hippo signaling pathway proteins Mst1, Mst2, p-Mob1, and LATS1 in gastric cancer cells
Summary
Gastric carcinoma is one of the most deadly cancers and it is associated with a high mortality rate [1,2,3,4]. The incidence of gastric cancer in Asia remains high, including in South Korea, [3,4], but a continuous diminution in gastric cancer occurrence has been reported in the developed countries of Europe and in America since the middle of the 20th century [3,4]. The attack rate of gastric cancer has constantly diminished over the last century, this cancer remains a critical cause of morbidity and mortality globally due to its unclear pathogenesis. It is imperative to find a novel effective remedy to obtain improved clinical results in patients with gastric cancer
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