Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer
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...
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MDPI AG
2019-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/20/19/4709 |
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| author | Seong-Hun Kim Hua Jin Ruo Yu Meng Da-Yeah Kim Yu Chuan Liu Ok Hee Chai Byung Hyun Park Soo Mi Kim |
| author_facet | Seong-Hun Kim Hua Jin Ruo Yu Meng Da-Yeah Kim Yu Chuan Liu Ok Hee Chai Byung Hyun Park Soo Mi Kim |
| author_sort | Seong-Hun Kim |
| collection | DOAJ |
| description | 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. |
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| issn | 1422-0067 |
| language | English |
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| spelling | doaj.art-098852b82a354918a8075acbca83ab192022-12-22T03:05:47ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-09-012019470910.3390/ijms20194709ijms20194709Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric CancerSeong-Hun Kim0Hua Jin1Ruo Yu Meng2Da-Yeah Kim3Yu Chuan Liu4Ok Hee Chai5Byung Hyun Park6Soo Mi Kim7Department of Internal Medicine, Chonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Physiology, Chonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Physiology, Chonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Physiology, Chonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Physiology, Chonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Anatomy and Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Biochemistry, Chonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Physiology, Chonbuk National University Medical School, Jeonju 54907, KoreaThe 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.https://www.mdpi.com/1422-0067/20/19/4709ursolic acidHippo signalinggastric cancer cellsproliferationmetastasis |
| spellingShingle | Seong-Hun Kim Hua Jin Ruo Yu Meng Da-Yeah Kim Yu Chuan Liu Ok Hee Chai Byung Hyun Park Soo Mi Kim Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer International Journal of Molecular Sciences ursolic acid Hippo signaling gastric cancer cells proliferation metastasis |
| title | Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer |
| title_full | Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer |
| title_fullStr | Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer |
| title_full_unstemmed | Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer |
| title_short | Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer |
| title_sort | activating hippo pathway via rassf1 by ursolic acid suppresses the tumorigenesis of gastric cancer |
| topic | ursolic acid Hippo signaling gastric cancer cells proliferation metastasis |
| url | https://www.mdpi.com/1422-0067/20/19/4709 |
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