MiR-18a Promotes Glioblastoma Development by Down-regulating ALOXE3-mediated Ferroptotic and Anti-migration Activities

Overview

Journal Oncogenesis

Date 2021 Feb 13

PMID 33579899

Citations 36

Authors

Xinzhi Yang

Jiangang Liu

Chenci Wang

Kenneth King-Yip Cheng

Hongchao Xu

Qingzhong Li

Tian Hua

Xue Jiang

Lili Sheng

Jie Mao

Zhuohao Liu

Affiliations

Soon will be listed here.

Abstract

The development of glioblastoma (GBM) is typically accompanied by marked changes in lipid metabolism. Oxylipins and their catalyzed enzymes lipoxygenases (LOXs) have been shown to participate in the development of cancers via multiple pathways, while the understanding of LOXs in GBM remains enigmatic. Thus, we aimed to explore the expression and functional roles of LOXs in the development of GBM. Here we showed that ALOXE3 was markedly down-regulated in human GBM. Knockdown of ALOXE3 in GBM cells fostered the orthotopic tumor growth and shortened lifespan in mice. ALOXE3 deficiency rendered GBM cells resistant to p53-SLC7A11 dependent ferroptosis, promoting GBM cell survival. Mechanistically, miR-18a directly targeted ALOXE3 and suppressed its expression and functions in GBM cells. Furthermore, ALOXE3 silencing promoted 12-hydroxyeicosatetraenoic acids (12-HETE) secretion from GBM cells, in turn, 12-HETE enhanced migration of GBM cells by activating G-protein-coupled receptor (GPCR)-PI3K-Akt pathway in an autocrine manner. Altogether, miR-18a/ALOXE3 axis exerts tumor promoting functions by regulating ferroptosis and migration of GBM cells. Targeting miR-18a/ALOXE3 axis may provide novel therapeutic approaches for GBM treatment.

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