Browse > Article
http://dx.doi.org/10.7314/APJCP.2013.14.9.5199

Effects of the Hippo Signaling Pathway in Human Gastric Cancer  

Zhou, Guang-Xi (Department of Gastroenterology, The Affiliated Hospital of Qingdao University Medical College)
Li, Xiao-Yu (Department of Gastroenterology, The Affiliated Hospital of Qingdao University Medical College)
Zhang, Qi (Department of Gastroenterology, The Affiliated Hospital of Qingdao University Medical College)
Zhao, Kun (Department of Gastroenterology, The Affiliated Hospital of Qingdao University Medical College)
Zhang, Cui-Ping (Department of Gastroenterology, The Affiliated Hospital of Qingdao University Medical College)
Xue, Chang-Hu (College of Food Science and Engineering, Ocean University of China)
Yang, Kun (The Core Laboratory, The Affiliated Hospital of Qingdao University Medical College)
Tian, Zi-Bin (Department of Gastroenterology, The Affiliated Hospital of Qingdao University Medical College)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.14, no.9, 2013 , pp. 5199-5205 More about this Journal
Abstract
Background/Aim: The Hippo signaling pathway is a newly discovered and conserved signaling cascade, which regulates organ size control by governing cell proliferation and apoptosis. This study aimed to investigate its effects in human gastric cancer. Methods: Tumor tissues (n=60), adjacent non-tumor tissues (n=60) and normal tissues (n=60) were obtained from the same patients with primary gastric cancer (GC). In addition, 70 samples of chronic atrophic gastritis (CAG) tissues were obtained from patients with intestinal metaplasia (IM) by endoscopic biopsy. Hippo signaling molecules, including Mst1, Lats1, YAP1, TAZ, TEAD1, Oct4 and CDX2, were determined by quantitative polymerase chain reaction (qPCR). Protein expression of Mst1, Lats1, YAP1, TEAD1 and CDX2 was assessed by immunohistochemistry and Western blotting. Results: Mst1, Lats1 and Oct4 mRNA expression showed an increasing tendency from GC tissues to normal gastric tissues, while the mRNA expression of YAP1, TAZ and TEAD1 was up-regulated (all P<0.01). Mst1 and Lats1 protein expression presented a similar trend with their mRNA expression. In addition, YAP1 and TEAD1 protein expression in GC was significantly higher than in the other groups (all P<0.01). CDX2 mRNA and protein expression in the CAG group were higher than in the other groups (all P<0.01). In GC, mRNA expression of Mst1, Lats1, Oct4, YAP1, TAZ, TEAD1 and CDX2 had a close correlation with lymphatic metastasis and tumor TNM stage (all P<0.01). Furthermore, protein expression of Mst1, Lats1, YAP1, TAZ, TEAD1 and CDX2 had a close correlation between each other (P<0.05). Conclusion: The Hippo signaling pathway is involved in the development, progression and metastasis of human gastric cancer. Therefore, manipulation of Hippo signaling molecules may be a potential therapeutic strategy for gastric cancer.
Keywords
Hippo signaling pathway; gastric cancer; chronic atrophic gastritis; intestinal metaplasia;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Freund JN, Domon-Dell C, Kedinger M, Duluc I (1998). The Cdx-1 and Cdx-2 homeobox genes in the intestine. Biochem Cell Biol, 76, 957-69   DOI
2 Barros R, da Costa LT, Pinto-de-Sousa J, et al (2011). CDX2 auto-regulation in human intestinal metaplasia of the stomach: impact on the stability of the phenotype. Gut, 60, 290-8.   DOI   ScienceOn
3 Harvey KF, Pfleger CM, Hariharan IK (2003). The Drosophila Mst Ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell, 114, 457-67.   DOI   ScienceOn
4 Kang JM, Lee BH, Kim N, et al (2011). CDX1 and CDX2 expression in intestinal metaplasia, dysplasia and gastric cancer. J Korean Med Sci, 26, 647-53.   DOI
5 Nishioka N, Inoue K, Adachi K, et al (2009). The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell, 16, 398-410.   DOI   ScienceOn
6 Liu X, Zhang X, Zhan Q, et al (2012). CDX2 serves as a Wnt signaling inhibitor and is frequently methylated in lung cancer. Cancer Biol Ther, 13, 1152-7.   DOI
7 Matsuoka J, Yashiro M, Sakurai K, et al (2012). Role of the stemness factors sox2, oct3/4, and nanog in gastric carcinoma. J Surg Res, 174, 130-5.   DOI   ScienceOn
8 Morrow DJ, Avissar NE, Toia L, et al (2009). Pathogenesis of Barrett's esophagus: Bile acids inhibit the Notch signaling pathway with induction of CDX2 gene expression in human esophagea cells. Surgery, 146, 714-22.   DOI   ScienceOn
9 Pan D (2010). The hippo signaling pathway in development and cancer. Dev Cell, 19, 491-505.   DOI   ScienceOn
10 Tajima Y, Yamazaki K, Makino R, et al (2006). Gastric and intestinal phenotypic marker expression in early differentiated-type tumors of the stomach: clinicopathologic significance and genetic Background. Clin Cancer Res, 12, 6469-79.   DOI   ScienceOn
11 Trosko JE (2006). From adult stem cells to cancer stem cells: Oct-4 Gene, cell-cell communication, and hormones during tumor promotion. Ann N Y Acad Sci, 1089, 36-58.   DOI   ScienceOn
12 Visser-Grieve S, Zhou Z, She YM, et al (2011). LATS1 Tumor suppressor is a novel actin-binding protein and negative regulator of actin polymerization. Cell Res, 21, 1513-6.   DOI   ScienceOn
13 Xu Z, Zhu J, Zhang Q, et al (2011). A breakdown of the Hippo pathway in gastric cancer. Hepatogastroenterology, 58, 1611-7.
14 Wei W, Zhang C, Zhang Q, et al (2012). Expression of Hippo signaling molecules in gastric carcinogenesis. World Chin J Digestol, 20, 3027-32.   DOI
15 Wen J, Park JY, Park KH, et al (2010). Oct4 and Nanog expression is associated with early stages of pancreatic carcinogenesis. Pancreas, 39, 622-6.   DOI   ScienceOn
16 Zhao B, Lei QY, Guan KL (2008). The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol, 20, 638 - 46.   DOI   ScienceOn
17 Yang L (2006). Incidence and mortality of gastric cancer in China. World J Gastroenterol, 12, 17-20.   DOI
18 Zeng Q, Hong W (2008). The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals. Cancer Cell, 13, 188-92.   DOI   ScienceOn
19 Zhao B, Wei X, Li W, et al (2007). Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev, 21, 2747-61.   DOI   ScienceOn
20 Zheng T, Wang J, Jiang H, et al (2011). Hippo signaling in oval cells and hepatocarcinogenesis. Cancer Letters, 302, 91-9.   DOI   ScienceOn
21 Chu J, Qin R, Wang N, et al (2011). Expression and significance of CDX2 and elaudin-3 in gastric carcinoma and paracancer tissue. J Clin Exp Pathol, 27, 1280-5.