RGS22 inhibits pancreatic adenocarcinoma cell migration through the G12/13 α subunit/F-actin pathway

Hu,Yanqiu; Xing,Jun; Chen,Ling; Zheng,Ying; Zhou,Zuomin

doi:10.3892/or.2015.4209

RGS22 inhibits pancreatic adenocarcinoma cell migration through the G12/13 α subunit/F-actin pathway

Authors:
- Yanqiu Hu
- Jun Xing
- Ling Chen
- Ying Zheng
- Zuomin Zhou
View Affiliations

Affiliations: Reproductive Medicine Center, Subei People's Hospital, Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China, Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China, Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Department of Histology and Embryology, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China
Published online on: August 19, 2015 https://doi.org/10.3892/or.2015.4209
Pages: 2507-2514

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

Pancreatic cancer is characterized by the potential for local invasion, allowing it to spread during the early developmental stages of the disease. Regulator of G protein signaling 22 (RGS22) localizes to the cytoplasm in pancreatic adenocarcinoma tissue. We overexpressed RGS22 in the human pancreatic cancer cell line BXPC-3. Cells that overexpressed RGS22 had much lower wound-healing rates and greatly reduced migration compared to the control cells. Conversely, cells in which RGS22 expression had been downregulated had higher wound-healing rates and migration than the control cells. These results confirmed that RGS22 expression suppresses pancreatic adenocarcinoma cell migration. Pull-down and coimmunoprecipitation assays revealed that RGS22 had specific interactions with the heterotrimeric G protein G12 α subunit (GNA12) and GNA13 in the cells. We also demonstrated that in the presence of higher RGS22 expression, the cell deformation and F-actin formation caused by lysophosphatidic acid treatment, is delayed. Constitutively active Gα subunits did not accelerate GTP hydrolysis to GDP. We did not investigate the function of RGS22 as a negative regulator of heterotrimeric G12/13 protein signaling. Our data demonstrate that RGS22 acts as a tumor suppressor, repressing human pancreatic adenocarcinoma cell migration by coupling to GNA12/13, which in turn leads to inhibition of stress fiber formation.

View Figures

View References

1	Bardeesy N, Sharpless NE, DePinho RA and Merlino G: The genetics of pancreatic adenocarcinoma: A roadmap for a mouse model. Semin Cancer Biol. 11:201–218. 2001. View Article : Google Scholar : PubMed/NCBI
2	Zhang XJ, Ye H, Zeng CW, He B, Zhang H and Chen YQ: Dysregulation of miR-15a and miR-214 in human pancreatic cancer. J Hematol Oncol. 3:462010. View Article : Google Scholar : PubMed/NCBI
3	Hu Y, Xing J, Chen L, Guo X, Du Y, Zhao C, Zhu Y, Lin M, Zhou Z and Sha J: RGS22, a novel testis-specific regulator of G-protein signaling involved in human and mouse spermiogenesis along with GNA12/13 subunits. Biol Reprod. 79:1021–1029. 2008. View Article : Google Scholar : PubMed/NCBI
4	Hu Y, Xing J, Wang L, Huang M, Guo X, Chen L, Lin M, Zhou Y, Liu Z, Zhou Z, et al: RGS22, a novel cancer/testis antigen, inhibits epithelial cell invasion and metastasis. Clin Exp Metastasis. 28:541–549. 2011. View Article : Google Scholar : PubMed/NCBI
5	Fokas E, Engenhart-Cabillic R, Daniilidis K, Rose F and An HX: Metastasis: The seed and soil theory gains identity. Cancer Metastasis Rev. 26:705–715. 2007. View Article : Google Scholar : PubMed/NCBI
6	Liotta LA, Steeg PS and Stetler-Stevenson WG: Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation. Cell. 64:327–336. 1991. View Article : Google Scholar : PubMed/NCBI
7	Orr FW, Wang HH, Lafrenie RM, Scherbarth S and Nance DM: Interactions between cancer cells and the endothelium in metastasis. J Pathol. 190:310–329. 2000. View Article : Google Scholar : PubMed/NCBI
8	Hu J and Verkman AS: Increased migration and metastatic potential of tumor cells expressing aquaporin water channels. FASEB J. 20:1892–1894. 2006. View Article : Google Scholar : PubMed/NCBI
9	Kelly P, Stemmle LN, Madden JF, Fields TA, Daaka Y and Casey PJ: A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion. J Biol Chem. 281:26483–26490. 2006. View Article : Google Scholar : PubMed/NCBI
10	Kelly P, Moeller BJ, Juneja J, Booden MA, Der CJ, Daaka Y, Dewhirst MW, Fields TA and Casey PJ: The G12 family of heterotrimeric G proteins promotes breast cancer invasion and metastasis. Proc Natl Acad Sci USA. 103:8173–8178. 2006. View Article : Google Scholar : PubMed/NCBI
11	Bian D, Mahanivong C, Yu J, Frisch SM, Pan ZK, Ye RD and Huang S: The G12/13-RhoA signaling pathway contributes to efficient lysophosphatidic acid-stimulated cell migration. Oncogene. 25:2234–2244. 2006. View Article : Google Scholar
12	Radhika V, Onesime D, Ha JH and Dhanasekaran N: Galpha13 stimulates cell migration through cortactin-interacting protein Hax-1. J Biol Chem. 279:49406–49413. 2004. View Article : Google Scholar : PubMed/NCBI
13	Mao H, Zhao Q, Daigle M, Ghahremani MH, Chidiac P and Albert PR: RGS17/RGSZ2, a novel regulator of Gi/o, Gz, and Gq signaling. J Biol Chem. 279:26314–26322. 2004. View Article : Google Scholar : PubMed/NCBI
14	Choi KU, Yun JS, Lee IH, Heo SC, Shin SH, Jeon ES, Choi YJ, Suh DS, Yoon MS and Kim JH: Lysophosphatidic acid-induced expression of periostin in stromal cells: Prognoistic relevance of periostin expression in epithelial ovarian cancer. Int J Cancer. 128:332–342. 2011. View Article : Google Scholar
15	Yatomi Y, Igarashi Y, Yang L, Hisano N, Qi R, Asazuma N, Satoh K, Ozaki Y and Kume S: Sphingosine 1-phosphate, a bioactive sphingolipid abundantly stored in platelets, is a normal constituent of human plasma and serum. J Biochem. 121:969–973. 1997. View Article : Google Scholar : PubMed/NCBI
16	Roffers-Agarwal J, Xanthos JB and Miller JR: Regulation of actin cytoskeleton architecture by Eps8 and Abi1. BMC Cell Biol. 6:362005. View Article : Google Scholar : PubMed/NCBI
17	Yadav D and Lowenfels AB: The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 144:1252–1261. 2013. View Article : Google Scholar : PubMed/NCBI
18	Doi Y, Yashiro M, Yamada N, Amano R, Noda S and Hirakawa K: VEGF-A/VEGFR-2 signaling plays an important role for the motility of pancreas cancer cells. Ann Surg Oncol. 19:2733–2743. 2012. View Article : Google Scholar
19	Yamada T, Sato K, Komachi M, Malchinkhuu E, Tobo M, Kimura T, Kuwabara A, Yanagita Y, Ikeya T, Tanahashi Y, et al: Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1. J Biol Chem. 279:6595–6605. 2004. View Article : Google Scholar
20	Hage B, Meinel K, Baum I, Giehl K and Menke A: Rac1 activation inhibits E-cadherin-mediated adherens junctions via binding to IQGAP1 in pancreatic carcinoma cells. Cell Commun Signal. 7:232009. View Article : Google Scholar : PubMed/NCBI
21	Offermanns S: G-proteins as transducers in transmembrane signalling. Prog Biophys Mol Biol. 83:101–130. 2003. View Article : Google Scholar : PubMed/NCBI