Peroxisome proliferator‑activated receptor‑γ inhibits pancreatic cancer cell invasion and metastasis via regulating MMP‑2 expression through PTEN

Li,Yue; Zhang,Da‑Wei; Lin,Dian‑Qiang; Cao,Liang‑Qi

doi:10.3892/mmr.2015.4224

Peroxisome proliferator‑activated receptor‑γ inhibits pancreatic cancer cell invasion and metastasis via regulating MMP‑2 expression through PTEN

Authors:
- Yue Li
- Da‑Wei Zhang
- Dian‑Qiang Lin
- Liang‑Qi Cao
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China
Published online on: August 12, 2015 https://doi.org/10.3892/mmr.2015.4224
Pages: 6255-6260

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

The invasive and metastatic behavior of pancreatic cancer is associated with a poor prognosis. Therefore, understanding the molecular mechanisms underlying the invasion and metastasis of pancreatic cancer has important application values theoretically and clinically. In previous years, with increasing studies focusing on tumor pathogenesis, it has been revealed that peroxisome proliferator‑activated receptor‑γ (PPARγ) and phosphatase and tensin homolog (PTEN) are closely associated with the occurrence and development of pancreatic cancer. Thus, in the present study, a scratch wound assay, western blotting and transwell assays were used to investigate their function. The scratch wound assay demonstrated that treatment with the PPARγ ligand rosiglitazone (RGZ) could reduce the movement and migration of pancreatic cancer cells. Western blotting results indicated that while RGZ inhibited the expression of matrix metalloproteinase (MMP)‑2, PPARγ inhibitors promoted MMP‑2 expression. However, PPARγ ligands and inhibitors did not affect the expression of MMP‑9. Further investigation indicated that the regulation of MMP‑2 by PPARγ activation occurred through PTEN. In addition, PPARγ activation promoted PTEN expression, thereby inhibiting the expression of MMP‑2. Subsequent transwell experiments demonstrated that RGZ treatment significantly inhibited the invasiveness of pancreatic cancer cells and the inhibitory effect of RGZ was completely reversed by simultaneous transfection of the MMP‑2‑overexpressing vector, which increased the invasiveness of pancreatic cancer cells. Therefore, PPARγ activation can activate PTEN expression, thereby suppressing the expression of MMP‑2 and hence inhibiting the invasion and metastasis of pancreatic cancer cells.

View Figures

View References

1	Yachida S and Iacobuzio-Donahue CA: The pathology and genetics of metastatic pancreatic cancer. Arch Pathol Lab Med. 133:413–422. 2009.PubMed/NCBI
2	Huguet F, Girard N, Guerche CS, Hennequin C, Mornex F and Azria D: Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: A qualitative systematic review. J Clin Oncol. 27:2269–2277. 2009. View Article : Google Scholar : PubMed/NCBI
3	Koeffler HP: Peroxisome proliferator-activated receptor gamma and cancers. Clin Cancer Res. 9:1–9. 2003.PubMed/NCBI
4	Rumi MA, Sato H, Ishihara S, Kawashima K, Hamamoto S, Kazumori H, Okuyama T, Fukuda R, Nagasue N and Kinoshita Y: Peroxisome proliferator-activated receptor gamma ligand-induced growth inhibition of human hepatocellular carcinoma. Br J Cancer. 84:1640–1647. 2001. View Article : Google Scholar : PubMed/NCBI
5	Sasaki T, Fujimoto Y, Tsuchida A, Kawasaki Y, Kuwada Y and Chayama K: Activation of peroxisome proliferator-activated receptor gamma inhibits the growth of human pancreatic cancer. Pathobiology. 69:258–265. 2001. View Article : Google Scholar
6	Farrow B, O'Connor KL, Hashimoto K, Iwamura T and Evers BM: Selective activation of PPARgamma inhibits pancreatic cancer invasion and decreases expression of tissue plasminogen activator. Surgery. 134:206–212. 2003. View Article : Google Scholar : PubMed/NCBI
7	Hashimoto K, Ethridge RT and Evers BM: Peroxisome proliferator-activated receptor gamma ligand inhibits cell growth and invasion of human pancreatic cancer cells. Int J Gastrointest Cancer. 32:7–22. 2002. View Article : Google Scholar
8	Koshiba T, Hosotani R, Wada M, Fujimoto K, Lee JU, Doi R, Arii S and Imamura M: Detection of matrix metalloproteinase activity in human pancreatic cancer. Surg Today. 27:302–304. 1997. View Article : Google Scholar : PubMed/NCBI
9	Bramhall SR, Neoptolemos JP, Stamp GW and Lemoine NR: Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol. 182:347–355. 1997. View Article : Google Scholar : PubMed/NCBI
10	Farrow B and Evers BM: Activation of PPARgamma increases PTEN expression in pancreatic cancer cells. Biochem Biophys Res Commun. 301:50–53. 2003. View Article : Google Scholar : PubMed/NCBI
11	Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ, Chen LZ, Tan HX, Li W, Bi J, et al: Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9. Hepatol Res. 39:177–186. 2009. View Article : Google Scholar : PubMed/NCBI
12	Nagase H and Woessner JF Jr: Matrix metalloproteinases. J Biol Chem. 274:21491–21494. 1999. View Article : Google Scholar : PubMed/NCBI
13	Li X, Yang Z, Song W, Zhou L, Li Q, Tao K, Zhou J, Wang X, Zheng Z, You N, Dou K and Li H: Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway. Int J Oncol. 43:793–802. 2013.PubMed/NCBI
14	Tian T, Nan KJ, Guo H, Wang WJ, Ruan ZP, Wang SH, Liang X and Lu CX: PTEN inhibits the migration and invasion of HepG2 cells by coordinately decreasing MMP expression via the PI3K/Akt pathway. Oncol Rep. 23:1593–600. 2010.PubMed/NCBI
15	Goggins M: Molecular markers of early pancreatic cancer. J Clin Oncol. 23:4524–4531. 2005. View Article : Google Scholar : PubMed/NCBI
16	Michalik L, Desvergne B and Wahli W: Peroxisome-proliferator-activated receptors and cancers: Complex stories. Nat Rev Cancer. 4:61–70. 2004. View Article : Google Scholar : PubMed/NCBI
17	Kristiansen G, Jacob J, Buckendahl AC, Grützmann R, Alldinger I, Sipos B, Klöppel G, Bahra M, Langrehr JM, Neuhaus P, et al: Peroxisome proliferator-activated receptor gamma is highly expressed in pancreatic cancer and is associated with shorter overall survival times. Clin Cancer Res. 12:6444–6451. 2006. View Article : Google Scholar : PubMed/NCBI
18	Toyota M, Miyazaki Y, Kitamura S, Nagasawa Y, Kiyohara T, Shinomura Y and Matsuzawa Y: Peroxisome proliferator-activated receptor gamma reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1. Life Sci. 70:1565–1575. 2002. View Article : Google Scholar : PubMed/NCBI
19	Kawa S, Nikaido T, Unno H, Usuda N, Nakayama K and Kiyosawa K: Growth inhibition and differentiation of pancreatic cancer cell lines by PPAR gamma ligand troglitazone. Pancreas. 24:1–7. 2002. View Article : Google Scholar
20	Itami A, Watanabe G, Shimada Y, Hashimoto Y, Kawamura J, Kato M, Hosotani R and Imamura M: Ligands for peroxisome proliferator-activated receptor gamma inhibit growth of pancreatic cancers both in vitro and in vivo. Int J Cancer. 94:370–376. 2001. View Article : Google Scholar : PubMed/NCBI
21	Yu J, Shen B, Chu ES, Teoh N, Cheung KF, Wu CW, Wang S, Lam CN, Feng H, Zhao J, et al: Inhibitory role of peroxisome proliferator-activated receptor gamma in hepatocarcinogenesis in mice and in vitro. Hepatology. 51:2008–2019. 2010. View Article : Google Scholar : PubMed/NCBI
22	Gomez DE, Alonso DF, Yoshiji H and Thorgeirsson UP: Tissue inhibitors of metalloproteinases: Structure, regulation and biological functions. Eur J Cell Biol. 74:111–122. 1997.PubMed/NCBI
23	Iki K, Takeo T, Kubozoe T, Aoki S, Hayashi J and Tsunoda T: Detection of serum MMPs in tumor-bearing hamsters. J Hepatobiliary Pancreat Surg. 9:478–484. 2002. View Article : Google Scholar : PubMed/NCBI
24	Nagakawa Y, Aoki T, Kasuya K, Tsuchida A and Koyanagi Y: Histologic features of venous invasion, expression of vascular endothelial growth factor and matrix metalloproteinase-2 and matrix metalloproteinase-9 and the relation with liver metastasis in pancreatic cancer. Pancreas. 24:169–178. 2002. View Article : Google Scholar : PubMed/NCBI
25	Jones G, Machado J Jr, Tolnay M and Merlo A: PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). Cancer Res. 61:5688–5691. 2001.PubMed/NCBI
26	Galli A, Ceni E, Crabb DW, Mello T, Salzano R, Grappone C, Milani S, Surrenti E, Surrenti C and Casini A: Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms. Gut. 53:1688–1697. 2004. View Article : Google Scholar : PubMed/NCBI