p120-catenin participates in the progress of gastric cancer through regulating the Rac1 and Pak1 signaling pathway

Li,Tong-Fei; Qin,Sheng-Hui; Ruan,Xu-Zhi; Wang,Xi

doi:10.3892/or.2015.4226

p120-catenin participates in the progress of gastric cancer through regulating the Rac1 and Pak1 signaling pathway

Authors:
- Tong-Fei Li
- Sheng-Hui Qin
- Xu-Zhi Ruan
- Xi Wang
View Affiliations

Affiliations: Department of Pathology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China, Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Pulmonary Disease of Ministry of Health of China, Wuhan, Hubei 430030, P.R. China
Published online on: August 26, 2015 https://doi.org/10.3892/or.2015.4226
Pages: 2357-2364

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

p120-catenin (p120), an E-cadherin regulator, has been implicated as central to a series of genetic and epigenetic changes that ultimately lead to tumor progression and metastasis. Ras-related C3 botulinum toxin substrate 1 (Rac1)and p21-activated kinases (PAKs) are effectors of p120. In the present study, we examined the expression of p120, Rac1 and Pak1 using immunohistochemistry in human gastric cancer tissues. Then, we used the gastric cancer SGC7901 and AGS cell lines to explore the possible mechanism of p120, Rac1 and Pak1 in the progress of gastric cancer. Western blotting was used to detect the expression of p120, Rac1 and Pak1 in the two cell lines. Next, p120 was silenced using p120 siRNA or overexpression of p120 by transfection of the plasmid p120 1A into the two cell types, western blotting was used to investigate the expression changes of Rac1 and Pak1. Furthermore, the effects of p120 siRNA-mediated knockdown or overexpression on the proliferation and invasive ability of gastric cancer cells were investigated using wound healing test and Matrigel invasion assays. The results showed that p120 was downregulated in both poorly differentiated group and well differentiated human gastric cancer. However, Rac1 and Pak1 were upregulated in poorly differentiated tissues and remain low in well differentiated gastric cancer tissues. In the two gastric cancer cell lines, although the expression of Rac1 and Pak1 remained unchanged after the p120 knockdown, the expressions of Rac1 and Pak1 protein were decreased after p120 overexpression in both SGC7901 and AGS cells. Furthermore, knockdown of p120 promoted gastric cancer cell proliferation and invasion; overexpression of p120 reduced the proliferation and invasion of gastric cancer cells. In conclusion, based on our results, we speculate that p120 participates in the progress of gastric cancer through regulating Rac1 and Pak1, which provides a potential prevention and a promising therapeutical approach for the patients with gastric cancer.

View Figures

View References

1	Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 57:43–66. 2007. View Article : Google Scholar : PubMed/NCBI
2	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
3	Gómez del Pulgar T, Bandrés E, Espina C, Valdés-Mora F, Pérez-Palacios R, García-Amigot F, García-Foncillas J and Lacal JC: Differential expression of Rac1 identifies its target genes and its contribution to progression of colorectal cancer. Int J Biochem Cell Biol. 39:2289–2302. 2007. View Article : Google Scholar : PubMed/NCBI
4	Rathinam R, Berrier A and Alahari SK: Role of Rho GTPases and their regulators in cancer progression. Front Biosci. 16:2561–2571. 2011. View Article : Google Scholar
5	Kumar R and Vadlamudi RK: Emerging functions of p21-activated kinases in human cancer cells. J Cell Physiol. 193:133–144. 2002. View Article : Google Scholar : PubMed/NCBI
6	Ong CC, Jubb AM, Haverty PM, Zhou W, Tran V, Truong T, Turley H, O'Brien T, Vucic D, Harris AL, et al: Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proc Natl Acad Sci USA. 108:7177–7182. 2011. View Article : Google Scholar : PubMed/NCBI
7	Vadlamudi RK, Adam L, Wang RA, Mandal M, Nguyen D, Sahin A, Chernoff J, Hung MC and Kumar R: Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem. 275:36238–36244. 2000. View Article : Google Scholar : PubMed/NCBI
8	Wang J-X, Zhou Y-N, Zou SJ, Ren TW and Zhang ZY: Correlations of p21-activated kinase 1 expression to clinicopathological features of gastric carcinoma and patients' prognosis. Chin J Cancer. 29:649–654. 2010. View Article : Google Scholar : PubMed/NCBI
9	Wu YJ, Tang Y, Li ZF, Li Z, Zhao Y, Wu ZJ and Su Q: Expression and significance of Rac1, Pak1 and Rock1 in gastric carcinoma. Asia Pac J Clin Oncol. 10:e33–e39. 2014. View Article : Google Scholar :
10	Reynolds AB, Roesel DJ, Kanner SB and Parsons JT: Transformation-specific tyrosine phosphorylation of a novel cellular protein in chicken cells expressing oncogenic variants of the avian cellular src gene. Mol Cell Biol. 9:629–638. 1989.PubMed/NCBI
11	Shibamoto S, Hayakawa M, Takeuchi K, Hori T, Miyazawa K, Kitamura N, Johnson KR, Wheelock MJ, Matsuyoshi N, Takeichi M, et al: Association of p120, a tyrosine kinase substrate, with E-cadherin/catenin complexes. J Cell Biol. 128:949–957. 1995. View Article : Google Scholar : PubMed/NCBI
12	Ferber A, Yaen C, Sarmiento E and Martinez J: An octapeptide in the juxtamembrane domain of VE-cadherin is important for p120ctn binding and cell proliferation. Exp Cell Res. 274:35–44. 2002. View Article : Google Scholar : PubMed/NCBI
13	Ishiyama N, Lee SH, Liu S, Li GY, Smith MJ, Reichardt LF and Ikura M: Dynamic and static interactions between p120 catenin and E-cadherin regulate the stability of cell-cell adhesion. Cell. 141:117–128. 2010. View Article : Google Scholar : PubMed/NCBI
14	Thoreson MA and Reynolds AB: Altered expression of the catenin p120 in human cancer: Implications for tumor progression. Differentiation. 70:583–589. 2002. View Article : Google Scholar : PubMed/NCBI
15	Anastasiadis PZ, Moon SY, Thoreson MA, Mariner DJ, Crawford HC, Zheng Y and Reynolds AB: Inhibition of RhoA by p120 catenin. Nat Cell Biol. 2:637–644. 2000. View Article : Google Scholar : PubMed/NCBI
16	Noren NK, Liu BP, Burridge K and Kreft B: p120 catenin regulates the actin cytoskeleton via Rho family GTPases. J Cell Biol. 150:567–580. 2000. View Article : Google Scholar : PubMed/NCBI
17	Grosheva I, Shtutman M, Elbaum M and Bershadsky AD: p120 catenin affects cell motility via modulation of activity of Rho-family GTPases: A link between cell-cell contact formation and regulation of cell locomotion. J Cell Sci. 114:695–707. 2001.PubMed/NCBI
18	Wong LE, Reynolds AB, Dissanayaka NT and Minden A: p120-catenin is a binding partner and substrate for group B Pak kinases. J Cell Biochem. 110:1244–1254. 2010. View Article : Google Scholar : PubMed/NCBI
19	Jaffer ZM and Chernoff J: p21-activated kinases: Three more join the Pak. Int J Biochem Cell Biol. 34:713–717. 2002. View Article : Google Scholar : PubMed/NCBI
20	Parrini MC, Lei M, Harrison SC and Mayer BJ: Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1. Mol Cell. 9:73–83. 2002. View Article : Google Scholar : PubMed/NCBI
21	Zhang X and Wang E: Impact of p120-catenin isforms 1A and 3A on epithelial mesenchymal transition of lung cancer cells expression e-cadherin in different subcellular locations. PLoS One. 9:880642014. View Article : Google Scholar
22	Tucker TA, Varga K, Bebok Z, Zsembery A, McCarty NA, Collawn JF, Schwiebert EM and Schwiebert LM: Transient transfection of polarized epithelial monolayers with CFTR and reporter genes using efficacious lipids. Am J Physiol Cell Physiol. 284:C791–C804. 2003. View Article : Google Scholar
23	Sun T, Tian H, Feng YG, Zhu YQ and Zhang WQ: Egr-1 promotes cell proliferation and invasion by increasing β-catenin expression in gastric cancer. Dig Dis Sci. 58:423–430. 2013.
24	Jiang G, Wang Y, Dai S, Liu Y, Stoecker M and Wang E and Wang E: P120-catenin isoforms 1 and 3 regulate proliferation and cell cycle of lung cancer cells via β-catenin and Kaiso respectively. PLoS One. 7:e303032012. View Article : Google Scholar
25	Zhang ZY and Ge HY: Micrometastasis in gastric cancer. Cancer Lett. 336:34–45. 2013. View Article : Google Scholar : PubMed/NCBI
26	Tang Y, Chen Z, Ambrose D, Liu J, Gibbs JB, Chernoff J and Field J: Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts. Mol Cell Biol. 17:4454–4464. 1997.PubMed/NCBI
27	Qu J, Cammarano MS, Shi Q, Ha KC, de Lanerolle P and Minden A: Activated PAK4 regulates cell adhesion and anchorage-independent growth. Mol Cell Biol. 21:3523–3533. 2001. View Article : Google Scholar : PubMed/NCBI
28	Thoreson MA, Anastasiadis PZ, Daniel JM, Ireton RC, Wheelock MJ, Johnson KR, Hummingbird DK and Reynolds AB: Selective uncoupling of p120^ctn from E-cadherin disrupts strong adhesion. J Cell Biol. 148:189–202. 2000. View Article : Google Scholar : PubMed/NCBI
29	Zhang Y, Zhao Y, Jiang G, Zhang X, Zhao H, Wu J, Xu K and Wang E: Impact of p120-catenin isoforms 1A and 3A on epithelial mesenchymal transition of lung cancer cells expressing E-cadherin in different subcellular locations. PLoS One. 9:e880642014. View Article : Google Scholar : PubMed/NCBI
30	Liu Y, Chen N, Cui X, Zheng X, Deng L, Price S, Karantza V and Minden A: The protein kinase Pak4 disrupts mammary acina architecture and promotes mammary tumorigenesis. Oncogene. 29:883–894. 2010. View Article : Google Scholar