Published online Sep 14, 2014. doi: 10.3748/wjg.v20.i34.11977
Revised: February 10, 2014
Accepted: April 30, 2014
Published online: September 14, 2014
Gastric cancer (GC) is the fourth most common cancer in the world and the second cause of cancer-related death. Gastric carcinogenesis is a multifactorial process, in which environmental and genetic factors interact to activate multiple intracellular signals thus leading to uncontrolled growth and survival of GC cells. One such a pathway is regulated by proteinase activated-receptors (PARs), seven transmembrane-spanning domain G protein-coupled receptors, which comprise four receptors (i.e., PAR-1, PAR-2, PAR-3, and PAR-4) activated by various proteases. Both PAR-1 and PAR-2 are over-expressed on GC cells and their activation triggers and/or amplifies intracellular pathways, which sustain gastric carcinogenesis. There is also evidence that expression of either PAR-1 or PAR-2 correlates with depth of wall invasion and metastatic dissemination and inversely with the overall survival of patients. Consistently, data emerging from experimental models of GC suggest that both these receptors can be important targets for therapeutic interventions in GC patients. In contrast, PAR-4 levels are down-regulated in GC and correlate inversely with the aggressiveness of GC, thus suggesting a negative role of this receptor in the control of GC. In this article we review the available data on the expression and role of PARs in GC and discuss whether manipulation of PAR-driven signals may be useful for interfering with GC cell behavior.
Core tip: In recent years, a large body of evidence has been accumulated to support the role of proteinase activated-receptors (PARs) in the control of gastric cancer (GC). In particular, it has been demonstrated that both PAR-1 and PAR-2 may trigger intracellular signals which ultimately sustain gastric carcinogenesis, whereas the exact role of PAR-3 and PAR-4 in the initiation and progression of GC remains to be ascertained. Despite these promising and novel observations, further experimentation is needed to better characterize the mechanisms underlying the expression and function of PARs in GC and their potential as therapeutic targets.