Protease-activated receptor-2 (PAR-2) in cervical cancer proliferation

Sánchez‐Hernández, Pedro Ernesto; Ramírez‐Dueñas, Maria Guadalupe; Albarran-Somoza, Benibelks; García-Iglesias, Trinidad; Toro-Arreola, Alicia del; Franco-Topete, Ramón Antonio; Daneri-Navarro, ́Adrián

doi:10.1016/j.ygyno.2007.08.083

Cited by 24 publications

(26 citation statements)

References 31 publications

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“…Among the members of PARs, PAR2 is generally recognized to be activated by protease not by thrombin and is an important mediator of tumor progression (24). It has been reported that PAR2 expressed in gastric cancer cells is more likely to play an important role in cell growth and EGFR transactivation (25).…”

Section: Discussionmentioning

confidence: 99%

Activation of PAR2 or/and TLR4 promotes SW620 cell proliferation and migration via phosphorylation of ERK1/2

Zhou

Shucai³

et al. 2011

Oncol Rep

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Abstract. Protease-activated receptor 2 (PAR2) is a G-proteincoupled receptor and its activation has been associated with the pathogenetic progress in certain cancers. Toll-like receptor 4 (TLR4), one member of Toll-like receptors family, is mainly contributed to the innate immune response. However, recent studies have shown that TLR4 is aberrantly expressed in various types of carcinomas and may correlate with tumor progression. Previously, we reported that PAR2 could be expressed in human colon cancer cell line (SW620) and its activation by some stimulants was able to facilitate cell proliferation and migration. In our recent preliminary experiment, it was found that SW620 cells also had TLR4 expression. Thus, we considered that PAR2 and TLR4 could have some collaborative roles in SW620 cells. In the current study, the cross-inducible expression of PAR2 and TLR4 on SW620 cells was investigated, and the functional roles of their activation on the behavior of SW620 cells were evaluated. It was found that activation of PAR2 with PAR2-AP (PAR2 agonist, 100 μM) enhanced TLR4 releasement and vice versa. The activation of PAR2 or TLR4 (with LPS, 100 ng/ml) could promote SW620 cell proliferation and migration, and the phosphorylation of ERK1/2 but not p38MAPK, as well as the expression of interleukin 8 (IL-8) and tissue factor (TF). Whereas the caspase-7 expression was decreased under PAR2 or TLR4 activation. Furthermore, ERK1/2 inhibitor (U0126, at 10 μM) could intervene in all regulating effects of PAR2 or/and TLR4. Collectively, this study demonstrated that both PAR2 and TLR4 activation on SW620 cells can trigger the phosphorylation of ERK1/2, regulate the expression of IL-8, TF and caspase-7, thereby promote the proliferation and migration of cells.

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Section: Discussionmentioning

confidence: 99%

Activation of PAR2 or/and TLR4 promotes SW620 cell proliferation and migration via phosphorylation of ERK1/2

Zhou

Shucai³

et al. 2011

Oncol Rep

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“…The enhanced proliferation was suppressed by gabexate mesilate, a potent inhibitor of serine protease. Given that trypsin induced the proliferation of PAR-2-positive human pancreatic, colon, gastric, breast and cervical cancers in vitro (22)(23)(24)(25)(26)(27), we suggest that trypsin secreted by ICC cells has the same effect on PAR-2-positive ICC cells in an autocrine manner. This study is the first indication of the enhancement of proliferative activity by trypsin in PAR-2-positive ICC cells.…”

Section: Discussionmentioning

confidence: 84%

“…At the same time, the contribution of PAR-2 and the effect of active trypsin on signaling pathways influencing malignant tumors are still being studied (22)(23)(24)(25)(26)(27). With regard to tumorderived trypsin in primary malignant liver tumors, our previous study demonstrated trypsinogen immunoreactivity in ICC tissues but not in HCC tissues (28), and Lempinen et al (37) suggested that serum trypsinogen-2 was a useful marker for diagnosing patients with cholangiocarcinoma, superior to serum CA19-9 and CEA.…”

Section: Discussionmentioning

confidence: 99%

“…PAR-2 activation induces a number of physiologic processes, and its agonist, trypsin is considered a signaling molecule (21). PAR-2 expression has been found in certain human solid tumors, such as gastric, colon and pancreatic cancer (22)(23)(24)(25)(26). Furthermore, several studies have suggested that trypsin plays a pivotal role in proliferation and serves as a potent mitogen in PAR2-positive cancer cells (22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

“…PAR-2 expression has been found in certain human solid tumors, such as gastric, colon and pancreatic cancer (22)(23)(24)(25)(26). Furthermore, several studies have suggested that trypsin plays a pivotal role in proliferation and serves as a potent mitogen in PAR2-positive cancer cells (22)(23)(24)(25)(26). The proliferative effect of the PAR-2 signal is mediated by the MEK-MAP kinase cascade (23,27).…”

Section: Introductionmentioning

confidence: 99%

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Tumor-derived trypsin enhances proliferation of intrahepatic cholangiocarcinoma cells by activating protease-activated receptor-2

Nakanuma

2010

Int J Oncol

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Abstract. In primary malignant liver tumors, trypsinogenimmunoreactivity was present in 70% of intrahepatic cholangiocarcinoma (ICC) specimens, but absent in hepatocellular carcinoma (HCC) specimens. We suggest the secretion of trypsinogen to be a key difference in biological behavior between ICC and HCC cells. The purpose of this study was to investigate the secretion of tumor-derived trypsin and the expression of its specific receptor, protease-activated receptor-2 (PAR-2), in ICC using cell lines and surgical specimens. The expression of trypsinogen-1 mRNA was observed in three of four ICC cell lines, but none of three HCC cell lines. Western blot analysis detected trypsinogen-1 in serum-free conditioned medium from one of the ICC cell lines positive for the mRNA. Gelatin zymography revealed a gelatinolytic activity for trypsin, the activated form of trypsinogen, in the same conditioned medium. PAR-2 mRNA and protein were observed in ICC cell lines. The proliferative activity of ICC cells was increased by concentrations of trypsin as low as 10 nM, and peaked at 100 nM. The effect of trypsin was suppressed by a serine protease inhibitor, gabexate mesilate. PAR-2 expression was detected in 64% of ICC surgical specimens immunohistochemically. In addition, stroma fibroblasts expressed PAR-2 in 52% of ICC specimens. These results suggest that trypsinogen-1 contributes to the growth of ICC cells and also tumor-associated fibroblasts.

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