Differential expression of Protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples

Abstract

Protease activated receptors (PAR) form a family of G-protein coupled receptors (GPCR) encoding their own ligands and uniquely activated via proteolytic cleavage. Although proteases in general have been implicated in the remodeling of the extracellular tumor microenvironment, the role of cell surface receptors activated by proteolysis is now emerging. In our present study we investigated the expression pattern of protease activated receptor 1 hPar1 in ovarian carcinoma tissue samples. Abundant hPar1 mRNA and protein were detected in "low malignant potential" and in invasive carcinomas, regardless of the histological subtype. In contrast, no hPar1 expression was detected on the cell surface of normal ovarian epithelium. The differential expression pattern of hPar1 was shown by in situ hybridization, immunohistochemistry and semi-quantitative RT-PCR analyses. In early stages of ovarian carcinoma (Ia), the contra lateral normal ovary showed strong PAR1 expression as opposed to the lack of expression in the ovarian epithelium obtained from normal individuals. In parallel, we analyzed the expression pattern of ␣v␤5 integrin and of activated focal adhesion kinase (FAK), a major focal contact protein, in these tissues. Although abundant expression of ␣v␤5 integrin was observed in all tissues specimens examined, regardless of either normal or malignant, the level of activated FAK was differentially expressed. Phosphorylated FAK was seen in invasive ovarian carcinoma, but not in the normal ovarian epithelium. The abundant hPar1 levels in pathological malignant ovarian carcinoma is likely to transmit signals leading to the phosphorylation of FAK and thereby alterations in the integrin functional state. Altogether our data suggest that hPar1 and FAK cooperate to promote ovarian cancer malignancy.

Mechanotransduction of fluid stresses governs 3D cell migration

“…FAK also becomes autophosphorylated at Tyr 397 through binding with β1 integrins in endothelial cells in response to shear stress (24) and in breast adenocarcinoma cells when exposed to 3 μm/s IF as we have shown previously (17). Furthermore, phosphorylation of FAK at Tyr 397 is required for invadopodia formation for breast cancer cells (25), and FAK PY397 is differentially expressed in metastatic cervical carcinoma relative to noncancerous epithelium (26). FAK is required for mechanical stress-induced cell polarization (6,27), and the FAK-paxillin-vinculin signaling complex is required for rigidity sensing and durotaxis (9).…”

Activation of KLF8 Transcription by Focal Adhesion Kinase in Human Ovarian Epithelial and Cancer Cells

“…FAK plays a critical role in the regulation of cancer initiation, progression, and metastasis, and its aberrantly high expression and phosphorylation are directly correlated with the malignancy of a variety of human cancers (3,4,6,7,(11)(12)(13)(14). FAK expression or activity is barely detectable in normal human ovarian epithelium but highly elevated in ϳ70% of human ovarian tumors and is associated with high risk clinical features and poor patient survival (4,7).…”

“…FAK expression or activity is barely detectable in normal human ovarian epithelium but highly elevated in ϳ70% of human ovarian tumors and is associated with high risk clinical features and poor patient survival (4,7). In addition to SKOV3ip1, our recent studies have demonstrated that KLF8 is also highly overexpressed in several other human ovarian cancer cell lines and primary ovarian tumor tissues (26).…”

Design, synthesis and biological evaluation of new peptide-based ureas and thioureas as potential antagonists of the thrombin receptor PAR1

“…However, numerous studies have shown that PAR1 is overexpressed in invasive and metastatic tumors and that its expression levels directly correlate with the degree of invasiveness of the cancer [20][21][22][23][24][25][26][27][28]. Based on these facts, this receptor is starting to be also considered a promising target for cancer therapy [15], particularly in the search of angiogenesis inhibitors [29].…”