PLA2R1 mediates tumor suppression by activating JAK2
Menée in vitro et in vivo, cette étude française met en évidence des mécanismes par lesquels, en activant la signalisation JAK2, le gène PLA2R1 joue un rôle de suppresseur de tumeurs
Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described to regulate the replicative senescence, a telomerase-dependant proliferation arrest. The downstream PLA2R1 signaling and its role on cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Further, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This result inding was unexpected as the JAK2 pathway has been associated mainly with pro-tumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling.
http://cancerres.aacrjournals.org/content/early/2013/09/04/0008-5472.CAN-13-0318.abstract 2013