Phospholipase C gamma 1 represses colorectal cancer growth by inhibiting the Wnt/beta-catenin signaling axis

Abstract

As essential phospholipid signaling regulators, phospholipase C (PLC)s are activated by various extra cellular ligands and mediate intracellular signal transduction. PLC gamma 1 is involved in regulating various cancer cell functions. However, the precise in vivo link between PLC gamma 1 and cancer behavior remains undefined. To investigate the role of PLC gamma 1 in colorectal carcinogenesis, we generated an intestinal tissue-specific Plcg1 knock out (KO) in adenomatous polyposis coli (Apc)(Min/+) mice. Plcg1 deficiency in Apc(Min/+) mice showed earlier death, with a higher colorectal tumor incidence in both number and size than in wild-type mice. Mechanistically, inhibition of PLC gamma 1 increased the levels of its substrate phosphoinositol 4,5-bisphosphate (PIP2) at the plasma membrane and promoted the activation of Wnt receptor low-density lipoprotein receptor-related protein 6 (LRP6) by glycogen synthase kinase 3 beta (GSK3 beta) to enhance beta-catenin signaling. Enhanced cell proliferation and Wnt/beta-catenin signaling were observed in colon tumors from Plcg1 KO mice. Furthermore, low PLC gamma 1 expression was associated with a poor prognosis of colon cancer patients. Collectively, we demonstrated the role of PLC gamma 1 in vivo as a tumor suppressor relationship between the regulation of the PIP2 level and Wnt/beta-catenin-dependent intestinal tumor formation. (C) 2021 Elsevier Inc. All rights reserved.