As essential phospholipid signaling regulators, phospholipase C (PLC)s are activated by various extracellular ligands and mediate intracellular signal transduction. PLCγ1 is involved in regulating various cancer cell functions. However, the precise in vivo link between PLCγ1 and cancer behavior remains undefined. To investigate the role of PLCγ1 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 PLCγ1 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 3β (GSK3β) to enhance β-catenin signaling. Enhanced cell proliferation and Wnt/β-catenin signaling were observed in colon tumors from Plcg1 KO mice. Furthermore, low PLCγ1 expression was associated with a poor prognosis of colon cancer patients. Collectively, we demonstrated the role of PLCγ1 in vivo as a tumor suppressor relationship between the regulation of the PIP2 level and Wnt/β-catenin-dependent intestinal tumor formation.

作为重要的磷脂信号调节剂，磷脂酶 C (PLC) 被各种细胞外配体激活并介导细胞内信号转导。 PLCγ1参与调节多种癌细胞功能。然而，PLCγ1 与癌症行为之间的精确体内联系仍不清楚。为了研究 PLCγ1 在结直肠癌发生中的作用，我们在腺瘤性息肉病大肠杆菌 (Apc) ^Min/+小鼠中产生了肠道组织特异性Plcg1敲除 (KO)。 Plcg1缺陷的Apc ^Min/+小鼠表现出更早的死亡，与野生型小鼠相比，结直肠肿瘤的数量和大小发生率更高。从机制上讲，抑制 PLCγ1 会增加质膜上其底物磷酸肌醇 4,5-二磷酸 (PIP2) 的水平，并促进糖原合酶激酶 3β (GSK3β) 激活 Wnt 受体低密度脂蛋白受体相关蛋白 6 (LRP6) ) 增强 β-连环蛋白信号传导。在Plcg1 KO 小鼠的结肠肿瘤中观察到细胞增殖和 Wnt/β-catenin 信号传导增强。此外，PLCγ1低表达与结肠癌患者的不良预后相关。总的来说，我们证明了 PLCγ1 在体内作为 PIP2 水平调节与 Wnt/β-连环蛋白依赖性肠道肿瘤形成之间的肿瘤抑制关系的作用。