Role of c-Src activity in the regulation of gastric cancer cell migration

Yang,Yun; Bai,Zhi-Gang; Yin,Jie; Wu,Guo-Cong; Zhang,Zhong-Tao

doi:10.3892/or.2014.3188

Role of c-Src activity in the regulation of gastric cancer cell migration

Authors:
- Yun Yang
- Zhi-Gang Bai
- Jie Yin
- Guo-Cong Wu
- Zhong-Tao Zhang
View Affiliations

Affiliations: Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Xuanwu, Beijing 100050, P.R. China
Published online on: May 15, 2014 https://doi.org/10.3892/or.2014.3188
Pages: 45-49
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

Gastric cancer is associated with increased migration and invasion. In the present study, we explored the role of c-Src in gastric cancer cell migration and invasion. BGC-823 gastric cancer cells were used to investigate migration following treatment of these cells with the c-Src inhibitors, PP2 and SU6656. Migration and invasion were analyzed by wound healing and Transwell assays. Western blot analysis was used to detect the expression of MT1-MMP and VEGF-C, while the activity of MMP2 and MMP9 was monitored with gelatin zymography assay. Immunoprecipitation was used to detect interactions among furin, pro-MT1-MMP and pro-VEGF-C. MT1-MMP and VEGF-C expression levels were inhibited by PP2 and SU6656 treatment, in accordance with decreased c-Src activity. Similarly, the zymography assay demonstrated that the activity of MMP2 and MMP9 was decreased following PP2 or SU6656 treatment. Blockade of c-Src also inhibited the invasive and migratory capacity of BGC-823 cells. Notably, c-Src interacted with furin in vivo, while interactions between furin and its substrates, pro-MT1-MMP and pro-VEGF-C, were decreased by c-Src inhibitors. In conclusion, the interaction among furin and pro-MT1-MMP or pro-VEGF-C or other tumor-associated precursor enzymes can be regulated by c-Src activity, thus reducing or changing the expression of these enzymes in order to reduce the development of gastric cancer, invasion and metastasis.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Namikawa T and Hanazaki K: Clinicopathological features and treatment outcomes of metastatic tumors in the stomach. Surg Today. Jul 30–2013.(Epub ahead of print).
3	He CZ and Zhang KH: Serum protein and genetic tumor markers of gastric carcinoma. Asian Pac J Cancer Prev. 14:3437–3442. 2013. View Article : Google Scholar : PubMed/NCBI
4	Vey M, Schafer W, Berghofer S, Klenk HD and Garten W: Maturation of the trans-Golgi network protease furin: compartmentalization of propeptide removal, substrate cleavage, and COOH-terminal truncation. J Cell Biol. 127:1829–1842. 1994. View Article : Google Scholar : PubMed/NCBI
5	Anderson ED, VanSlyke JK, Thulin CD, Jean F and Thomas G: Activation of the furin endoprotease is a multiple-step process: requirements for acidification and internal propeptide cleavage. EMBO J. 16:1508–1518. 1997. View Article : Google Scholar : PubMed/NCBI
6	de Lartigue J, Polson H, Feldman M, et al: PIKfyve regulation of endosome-linked pathways. Traffic. 10:883–893. 2009.PubMed/NCBI
7	Kappert K, Meyborg H, Fritzsche J, et al: Proprotein convertase subtilisin/kexin type 3 promotes adipose tissue-driven macrophage chemotaxis and is increased in obesity. PLoS One. 8:e705422013. View Article : Google Scholar
8	Lopez de Cicco R, Bassi DE, Zucker S, et al: Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin. Cancer Res. 65:4162–4171. 2005.PubMed/NCBI
9	Komiyama T, Coppola JM, Larsen MJ, et al: Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules. J Biol Chem. 284:15729–15738. 2009. View Article : Google Scholar : PubMed/NCBI
10	Hilbig A: Src kinase and pancreatic cancer. Recent Results Cancer Res. 177:179–185. 2008. View Article : Google Scholar
11	Okamoto W, Okamoto I, Yoshida T, et al: Identification of c-Src as a potential therapeutic target for gastric cancer and of MET activation as a cause of resistance to c-Src inhibition. Mol Cancer Ther. 9:1188–1197. 2010. View Article : Google Scholar : PubMed/NCBI
12	Nam HJ, Im SA, Oh DY, et al: Antitumor activity of saracatinib (AZD0530), a c-Src/Abl kinase inhibitor, alone or in combination with chemotherapeutic agents in gastric cancer. Mol Cancer Ther. 12:16–26. 2013. View Article : Google Scholar : PubMed/NCBI
13	Summy JM and Gallick GE: Treatment for advanced tumors: SRC reclaims center stage. Clin Cancer Res. 12:1398–1401. 2006. View Article : Google Scholar : PubMed/NCBI
14	Lee M, Choy WC and Abid MR: Direct sensing of endothelial oxidants by vascular endothelial growth factor receptor-2 and c-Src. PLoS One. 6:e284542011. View Article : Google Scholar : PubMed/NCBI
15	Tekedereli I, Alpay SN, Tavares CD, et al: Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer. PLoS One. 7:e411712012. View Article : Google Scholar : PubMed/NCBI
16	Demidyuk IV, Shubin AV, Gasanov EV, et al: Alterations in gene expression of proprotein convertases in human lung cancer have a limited number of scenarios. PLoS One. 8:e557522013. View Article : Google Scholar : PubMed/NCBI
17	Page RE, Klein-Szanto AJ, Litwin S, et al: Increased expression of the pro-protein convertase furin predicts decreased survival in ovarian cancer. Cell Oncol. 29:289–299. 2007.PubMed/NCBI
18	Thomas G: Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol. 3:753–766. 2002. View Article : Google Scholar : PubMed/NCBI
19	Bassi DE, Mahloogi H, Lopez De Cicco R, et al: Increased furin activity enhances the malignant phenotype of human head and neck cancer cells. Am J Pathol. 162:439–447. 2003. View Article : Google Scholar : PubMed/NCBI
20	Strongin AY: Proteolytic and non-proteolytic roles of membrane type-1 matrix metalloproteinase in malignancy. Biochim Biophys Acta. 1803.133–141. 2010.PubMed/NCBI
21	Suboj P, Babykutty S, Valiyaparambil G, Nair RS, Srinivas P and Gopala S: Aloe emodin inhibits colon cancer cell migration/angiogenesis by downregulating MMP-2/9, RhoB and VEGF via reduced DNA binding activity of NF-κB. Eur J Pharm Sci. 45:581–591. 2012.PubMed/NCBI
22	Stacker SA, Caesar C and Baldwin ME: VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 7:186–191. 2001. View Article : Google Scholar : PubMed/NCBI
23	Tolde O, Rosel D, Mierke CT, et al: Neoplastic progression of the human breast cancer cell line G3S1 is associated with elevation of cytoskeletal dynamics and upregulation of MT1-MMP. Int J Oncol. 36:833–839. 2010.PubMed/NCBI
24	Iravani O, Tay BW, Chua PJ, Yip GW and Bay BH: Claudins and gastric carcinogenesis. Exp Biol Med (Maywood). 238:344–349. 2013. View Article : Google Scholar : PubMed/NCBI
25	Zucker S, Pei D, Cao J and Lopez-Otin C: Membrane type-matrix metalloproteinases (MT-MMP). Curr Top Dev Biol. 54:1–74. 2003. View Article : Google Scholar : PubMed/NCBI
26	Nakanishi Y, Ohara M, Domen H, Shichinohe T, Hirano S and Ishizaka M: Differences in risk factors between patterns of recurrence in patients after curative resection for advanced gastric carcinoma. World J Surg Oncol. 11:982013. View Article : Google Scholar
27	Parker MW, Hellman LM, Xu P, et al: Furin processing of semaphorin 3F determines its anti-angiogenic activity by regulating direct binding and competition for neuropilin. Biochemistry. 49:4068–4075. 2010. View Article : Google Scholar : PubMed/NCBI
28	Stawowy P, Blaschke F and Kilimnik A: Proprotein convertase PC5 regulation by PDGF-BB involves PI3-kinase/p70^s6-kinase activation in vascular smooth muscle cells. Hypertension. 39:399–406. 2002. View Article : Google Scholar : PubMed/NCBI