Table_2_LOXL2 Upregulation in Gliomas Drives Tumorigenicity by Activating Autophagy to Promote TMZ Resistance and Trigger EMT.doc

Glioma is the most prevalent primary brain tumor in adults and has an extremely unfavorable prognosis. As a member of the lysyl oxidase (LOX) family, lysyl-oxidase-like-2 (LOXL2) is known to play different roles in different tumors. However, the role of LOXL2 in glioma has not yet been fully elucidated. In the present study, we detected that LOXL2 was considerably upregulated in glioma and that LOXL2 upregulation was evidently related to glioma WHO grade, malignant molecular subtypes, and poor prognosis in glioma patients. Additionally, we found that LOXL2 not only promoted glioma cells proliferation, migration, invasion, and induced the epithelial-to-mesenchymal transition (EMT) process, but also reduced the sensitivity of glioma cells to temozolomide (TMZ). Furthermore, we identified that LOXL2 reduced TMZ sensitivity and induced EMT in glioma via the activation of autophagy. Mechanistically, LOXL2 enhanced Atg7 expression by promoting the phosphorylation of Erk1/2, leading to the activation of autophagy and regulation of EMT process and TMZ sensitivity through autophagy. Our study describes an LOXL2-Erk1/2-Atg7 signaling axis that influences glioma EMT and chemosensitivity through autophagy; moreover, LOXL2 may serve as a promising therapeutic target in the treatment of glioma.

胶质瘤（Glioma）是成人最常见的原发性脑肿瘤，预后极差。作为赖氨酰氧化酶（lysyl oxidase, LOX）家族成员，赖氨酰氧化酶样蛋白2（lysyl-oxidase-like-2, LOXL2）在不同肿瘤中发挥的作用不尽相同。然而，LOXL2在胶质瘤中的作用尚未完全阐明。本研究检测发现，LOXL2在胶质瘤中显著上调，且LOXL2的高表达与胶质瘤的世界卫生组织（WHO）分级、恶性分子亚型及患者不良预后显著相关。此外，本研究还发现，LOXL2不仅可促进胶质瘤细胞的增殖、迁移与侵袭，诱导上皮间质转化（epithelial-to-mesenchymal transition, EMT）过程，还可降低胶质瘤细胞对替莫唑胺（temozolomide, TMZ）的敏感性。进一步研究证实，LOXL2可通过激活自噬（autophagy）降低胶质瘤细胞对TMZ的敏感性并诱导EMT过程。从机制层面来看，LOXL2通过促进细胞外调节蛋白激酶1/2（Erk1/2）的磷酸化，上调自噬相关基因7（Atg7）的表达，进而激活自噬，并通过自噬调控EMT过程与TMZ敏感性。本研究揭示了一条通过自噬影响胶质瘤EMT过程与化疗敏感性的LOXL2-Erk1/2-Atg7信号轴；此外，LOXL2或可成为胶质瘤治疗的潜在靶点。