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

Abstract

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.

Combining bioinformatics techniques to explore the molecular mechanisms involved in pancreatic cancer metastasis and prognosis

“…The role of PPAR signalling pathway in pancreatic cancer metastasis has been reported in the literature. Li et al 16 have reported that activation of PPARγ can up‐regulate the tumour suppressor gene PTEN, thereby inhibiting the expression of MMP‐2, thus impairing the migration and invasion of pancreatic cancer cell lines. As the PI3K‐Akt signalling pathway is one of the star signalling pathways for extensive researches, its abnormal activation for promoting invasion and metastasis of pancreatic cancer has been confirmed by many studies 17,18 .…”

PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

“…Here, we present evidence of a novel regulatory mechanism for MTSS1 stabilization via the canonical tumor suppressor protein PTEN. PTEN expression has been found to be crucial in minimizing the lethality of PDAC through regulation of the PI3K/AKT pathway [22] ; however, its role in PDAC metastasis has only been briefly studied [23] , [24] , [25] . In this manuscript, we demonstrate that loss of PTEN in PDAC cells not only leads to a more invasive and migratory phenotype, but also results in decreased in MTSS1 expression.…”

VSP-17, a New PPARγ Agonist, Suppresses the Metastasis of Triple-Negative Breast Cancer via Upregulating the Expression of E-Cadherin

“…Therefore, PPARγ activation might be beneficial in TNBC therapy. Rosiglitazone, one of the thiazolidinediones, can inhibit metastasis in a murine model of hepatocellular carcinoma [ 31 ] and inhibit pancreatic cancer cell invasion and metastasis by regulating MMP-2 expression through phosphatase and tensin homolog (PTEN) [ 32 ]. There is also growing evidence that PPARγ agonist pioglitazone can inhibit NF-κB activation in cisplatin nephrotoxicity by reducing p65 acetylation via the AMPK-SIRT1/p300 pathway [ 33 ].…”