Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survival and potential therapeutic targets
“…Indeed, overexpression of uPA has been found in several types of cancer, including prostate, glioblastoma, melanoma, breast, colon, and lung (16)(17)(18)(19)(20)(21)(22)(23). Notably, in most of these cases, the increased expression of uPA is associated with increased metastatic potential and poor survival (24)(25)(26). We previously showed that uPA promotes invasiveness of prostate cancer cells in vitro and tumorigenicity in vivo (27).…”
Recent studies have shown that small interfering RNA (siRNA) silences genes at the transcriptional level in human cells. However, the therapeutic potential of siRNA-mediated transcriptional gene silencing remains unclear. Here, we show that siRNA targeted to the urokinase plasminogen activator (uPA) promoter induced epigenetic transcriptional silencing in human prostate cancer cells. This silencing resulted in a dramatic reduction of tumor cell invasion and angiogenesis in vitro. Furthermore, the results from a bioluminescence tumor/metastasis model showed that the silencing of uPA significantly inhibits prostate tumor growth and the incidence of lung metastasis. Our findings represent a potentially powerful new approach to not only epigenetic silencing of metastasis or growth-promoting genes as a cancer therapy, but also as a means to shed light on how aberrant de novo methylation during cancer progression might be targeted to specific sequences. [Cancer Res 2007;67(14):6637-46]
“…Indeed, overexpression of uPA has been found in several types of cancer, including prostate, glioblastoma, melanoma, breast, colon, and lung (16)(17)(18)(19)(20)(21)(22)(23). Notably, in most of these cases, the increased expression of uPA is associated with increased metastatic potential and poor survival (24)(25)(26). We previously showed that uPA promotes invasiveness of prostate cancer cells in vitro and tumorigenicity in vivo (27).…”
Recent studies have shown that small interfering RNA (siRNA) silences genes at the transcriptional level in human cells. However, the therapeutic potential of siRNA-mediated transcriptional gene silencing remains unclear. Here, we show that siRNA targeted to the urokinase plasminogen activator (uPA) promoter induced epigenetic transcriptional silencing in human prostate cancer cells. This silencing resulted in a dramatic reduction of tumor cell invasion and angiogenesis in vitro. Furthermore, the results from a bioluminescence tumor/metastasis model showed that the silencing of uPA significantly inhibits prostate tumor growth and the incidence of lung metastasis. Our findings represent a potentially powerful new approach to not only epigenetic silencing of metastasis or growth-promoting genes as a cancer therapy, but also as a means to shed light on how aberrant de novo methylation during cancer progression might be targeted to specific sequences. [Cancer Res 2007;67(14):6637-46]
“…Elevated levels of uPA (urokinase plasminogen activator) and its receptor, uPAR, have been associated with a negative prognosis (Ganesh et al, 1994) and distant metastases (Yang et al, 2000) of colorectal cancer. uPAR has also been localized to the invasive front of colon adenocarcinomas (Pyke et al, 1991).…”
Cathepsin B and pro-urokinase plasminogen activator (pro-uPA) localize to the caveolae of HCT 116 human colorectal carcinoma cells, an association mediated by active K-RAS. In this study, we established a stable HCT 116 cell line with a gene encoding antisense caveolin-1 (AS-cav-1) to examine the effects of caveolin-1, the main structural protein of caveolae, on the expression and localization of cathepsin B and pro-uPA, and their cell-surface receptors p11 and uPA receptor (uPAR), respectively. AS-cav-1 HCT 116 cells secreted less procathepsin B than control (empty vector) cells as measured by immunoblotting and pepsin activation of the proenzyme. Expression and secretion of pro-uPA was also downregulated in AS-cav-1 HCT 116 cells. Localization of cathepsin B and pro-uPA to caveolae was reduced in AS-cav-1 HCT 116 cells, and these cells expressed less total and caveolae-associated p11 and uPAR compared with control cells. Previous studies have shown that uPAR forms a complex with caveolin-1 and β1-integrin, and we here show that downregulation of caveolin-1 also suppressed the localization of β1-integrin to caveolae of these cells. Finally, downregulation of caveolin-1 in HCT 116 cells inhibited degradation of the extracellular matrix protein collagen IV and the invasion of these cells through Matrigel. Based on these results, we hypothesize that caveolin-1 affects the expression and localization of cathepsin B and pro-uPA, and their receptors, thereby mediating cell-surface proteolytic events associated with invasion of colon cancer cells.
“…However, the mechanism for the procession of gastric cancer is still poorly understood. The over-expression of uPA has been detected in various malignancies including breast (Miyake et al, 1999), prostate (Yang et al, 2000), colon (Duggan et al, 1995), and pancreatic (Lee et al, 2003b). Some data have shown that a high level of uPA in tumors is associated with a rapid disease progression and a poor prognosis (Solomayer et al, 1997;Bouchetm et al, 1998).…”
The regulatory mechanisms for the proliferation and the particular invasive phenotypes of stomach cancers are not still fully understood. Up-regulations of hepatocytes growth factor (HGF), its receptor (cMet), and urokinase-type plasminogen activator (uPA) are correlated with the development and metastasis of cancers. In order to investigate roles of HGF/c-Met signaling in tumor progression and metastasis in stomach cancers, we determined effects of a specific MEK1 inhibitor (PD098059) and a p38 kinase inhibitor (SB203580) on HGF-mediated cell proliferation and uPA expression in stomach cancer cell lines (NUGC-3 and MKN-28). HGF treatment induced the phosphorylations of ERK and p38 kinase in time-and dose-dependent manners. Pre-treatment with PD098059 reduced HGF-mediated cell proliferation and uPA secretion. In contrast, SB203580 pre-treatment enhanced cell proliferation and uPA secretion due to induction of ERK phosphorylation. Stable expression of dominant negative-MEK1 in NUGC-3 cells showed a decrease in HGF-mediated uPA secretion. These results suggest that interaction of a MEK/ERK and a p38 kinase might play an important role in proliferation and invasiveness of stomach cancer cells.
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