TY - JOUR
T1 - miR-18a promotes glioblastoma development by down-regulating ALOXE3-mediated ferroptotic and anti-migration activities
AU - Yang, Xinzhi
AU - Liu, Jiangang
AU - Wang, Chenci
AU - Cheng, Kenneth King yip
AU - Xu, Hongchao
AU - Li, Qingzhong
AU - Hua, Tian
AU - Jiang, Xue
AU - Sheng, Lili
AU - Mao, Jie
AU - Liu, Zhuohao
N1 - Funding Information:
This research was funded by the Young Scientists Fund of NSFC (grant number: 81900801), Project funded by China Postdoctoral Science Foundation (grant number: 2019M663000), and Shenzhen Basic Research Program (grant number: 20190805151748954 and 20190805131532394).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/2/12
Y1 - 2021/2/12
N2 - 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 Gs-protein-coupled receptor (GsPCR)-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.
AB - 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 Gs-protein-coupled receptor (GsPCR)-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.
UR - http://www.scopus.com/inward/record.url?scp=85100867356&partnerID=8YFLogxK
U2 - 10.1038/s41389-021-00304-3
DO - 10.1038/s41389-021-00304-3
M3 - Journal article
AN - SCOPUS:85100867356
SN - 2157-9024
VL - 10
JO - Oncogenesis
JF - Oncogenesis
IS - 2
M1 - 15
ER -
