PAR₁ plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway

Protease-activated receptor1 (PAR₁) is the first and prototype member of an established PAR family comprising four members. The role of PAR₁ in tumor biology has been established, and is characterized by a consistent direct correlation between overexpression of its levels and epithelial tumor aggressiveness. We have found that high expression of the human Par₁ (hPar₁) gene in epithelial tumors is controlled largely at the transcriptional level. This led us to assign Egr-1, a transcription activator, as an inducer of hPar₁, and p53, a tumor suppressor gene, as an inhibitor, both acting to achieve fine tuning of hPar₁ in prostate carcinoma. High PAR₁ levels maintain prosurvival signals in tumor cells while silencing or ablation of the gene induce apoptosis. Studies of our hPar₁ transgenic mice, which overexpress hPar₁ in the mammary glands, revealed a novel PAR ₁-induced β-catenin stabilization function. The components connecting PAR₁ to β-catenin stabilization have been determined, assigning at first G_α13 as a selective immediate component. The PAR₁-G_α13 axis recruits disheveled (DVL), an upstream signaling partner of the canonical Wnt signaling pathway. Silencing of DVL by siRNA-DVL potently abrogates PAR₁-induced β-catenin stabilization, demonstrating its critical role in the process. We, thus, propose that transcriptional regulation of hPar₁ gene over expression in epithelia malignancies initiates a novel signaling pathway, directly connecting to β-catenin stabilization, a core event in both tumorigenesis and developmental processes.