WIPI2自噬与肿瘤研究进展

Research Progress on WIPI2 Autophagy and Tumors

摘要: 自噬功能失调与肿瘤的发生、演进密切相关。肿瘤始发阶段，自噬可通过维持基因组稳定性抑制肿瘤发生，而肿瘤演进阶段，保护性自噬则可支撑肿瘤细胞存活，加速恶性进程。WD重复结构域磷脂酰肌醇相互作用蛋白2 (WD Repeat Domain, Phosphoinositide Interacting 2, WIPI2)是酵母ATG18基因的哺乳动物同源物，属于WD40重复蛋白家族的WIPI亚家族，具有7叶β-螺旋桨保守结构，可通过结合磷脂酰肌醇3-磷酸(PI3P)或磷脂酰肌醇4-磷酸(PI4P)，作为分子支架招募下游自噬相关复合物，在经典自噬、选择性自噬及非经典自噬通路中均发挥核心调控作用。除自噬功能外，WIPI2还参与整合素循环调控、胚胎发育等生理过程，其功能异常与神经发育障碍、自身免疫性疾病及肿瘤等多种疾病密切相关。近年来，研究表明，WIPI2在肝细胞癌、结直肠癌、胰腺癌、非小细胞肺癌等多种肿瘤中异常高表达，通过调控自噬通量参与肿瘤的增殖、侵袭转移、代谢重编程及治疗耐药过程。在RAS突变肿瘤中，WIPI2作为PI4P效应分子介导非经典自噬通路激活，促进肿瘤代谢适应；在化疗、靶向治疗耐药肿瘤中，WIPI2通过增强自噬活性降解药物诱导的受损物质，减少肿瘤细胞凋亡，靶向抑制WIPI2及其上下游通路可显著逆转耐药。文章系统梳理WIPI2的分子结构、生理功能及调控机制，重点阐述其在肿瘤自噬、进展及耐药中的作用研究进展，以期为肿瘤自噬靶向治疗提供潜在靶标与新的研究方向。

Abstract: Dysregulated autophagy is closely associated with tumor initiation and progression. At the tumor initiation stage, autophagy suppresses tumorigenesis by maintaining genomic stability, whereas at the tumor progression stage, protective autophagy sustains tumor cell survival and accelerates malignant progression. WD repeat domain phosphoinositide-interacting protein 2 (WIPI2), the mammalian ortholog of yeast ATG18, belongs to the WIPI subfamily of the WD40 repeat protein family and harbors a conserved seven-bladed β-propeller domain. By binding to phosphatidylinositol 3-phosphate (PI3P) or phosphatidylinositol 4-phosphate (PI4P), WIPI2 functions as a molecular scaffold that recruits downstream autophagy-associated complexes, thereby exerting core regulatory functions in canonical, selective, and non-canonical autophagy pathways. Beyond its autophagic functions, WIPI2 participates in physiological processes including integrin recycling and embryonic development, and its dysfunction is tightly linked to neurodevelopmental disorders, autoimmune diseases, and various tumors. Recent studies have demonstrated that WIPI2 is aberrantly overexpressed in multiple tumors such as hepatocellular carcinoma, colorectal cancer, pancreatic cancer, and non-small cell lung cancer. It modulates autophagic flux to participate in tumor proliferation, invasion, metastasis, metabolic reprogramming, and therapeutic resistance. In RAS-mutated tumors, WIPI2 serves as a PI4P effector molecule to activate non-canonical autophagy and promote tumor metabolic adaptation. In chemotherapy- and targeted therapy-resistant tumors, WIPI2 enhances autophagic activity to degrade drug-induced damaged material and reduce tumor cell apoptosis; targeted inhibition of WIPI2 and its upstream and downstream pathways can significantly reverse therapeutic resistance. This review systematically summarizes the molecular structure, physiological functions, and regulatory mechanisms of WIPI2, with a focus on its biological functions in tumor autophagy, progression, and drug resistance, aiming to provide novel potential targets and research directions for autophagy-targeted tumor therapy.