Nuclear transport of phosphorylated LanCL2 promotes invadopodia formation and tumor progression of glioblastoma by activating STAT3/Cortactin signaling

Hua-Fu Zhao; Yun-Sheng Liu; Jing Wang; Chang-Peng Wu; Xiu-Ming Zhou; Lin-Rong Cai; Jing Liu; Xiao-Jia Liu; Yan-Wen Xu; Wei-Ping Li; Guo-Dong Huang

doi:10.1016/j.jare.2024.03.007

Nuclear transport of phosphorylated LanCL2 promotes invadopodia formation and tumor progression of glioblastoma by activating STAT3/Cortactin signaling

J Adv Res. 2024 Mar 15:S2090-1232(24)00107-3. doi: 10.1016/j.jare.2024.03.007. Online ahead of print.

Authors

Hua-Fu Zhao¹, Yun-Sheng Liu², Jing Wang³, Chang-Peng Wu⁴, Xiu-Ming Zhou⁵, Lin-Rong Cai², Jing Liu⁶, Xiao-Jia Liu², Yan-Wen Xu², Wei-Ping Li², Guo-Dong Huang⁷

Affiliations

¹ Department of Neurosurgery, Institute of Translational Medicine, Shenzhen University First Affiliated Hospital, Shenzhen Second People's Hospital, Shenzhen 518035, China. Electronic address: zhaohf0416@email.szu.edu.cn.
² Department of Neurosurgery, Institute of Translational Medicine, Shenzhen University First Affiliated Hospital, Shenzhen Second People's Hospital, Shenzhen 518035, China.
³ Department of Neurosurgery/Neuro-oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
⁴ Department of Neurosurgery, Shenzhen Longhua New District People's Hospital, Shenzhen 518109, China.
⁵ Epilepsy Center, Guangdong 999 Brain Hospital, Guangzhou 510510, China.
⁶ Department of Pathology, Shenzhen University First Affiliated Hospital, Shenzhen Second People's Hospital, Shenzhen 518035, China.
⁷ Department of Neurosurgery, Institute of Translational Medicine, Shenzhen University First Affiliated Hospital, Shenzhen Second People's Hospital, Shenzhen 518035, China. Electronic address: huangguodong@email.szu.edu.cn.

PMID: 38492734
DOI: 10.1016/j.jare.2024.03.007

Abstract

Introduction: Our previous study showed that the abscisic acid receptor lanthionine synthetase C-like 2 (LanCL2) is a significant prognostic factor for overall survival in young glioblastoma patients. However, the role of LanCL2 in glioblastoma remains unclear yet.

Objectives: This study aims to investigate the role of LanCL2 in regulating in-vitro cell invasion and in-vivo tumor progression of glioblastoma and its underlying mechanism.

Methods: Tyrosine 198 or 295 residue of LanCL2 was mutated using site-directed mutagenesis to block its phosphorylation. The role of LanCL2 in glioblastoma was investigated using transwell or 3D invasion assay, matrix degradation assay and intracranial xenograft model.

Results: This study showed that nuclear transport of LanCL2 was enhanced by overexpression of LanCL2 or its ligand abscisic acid in glioblastoma cells. Knockdown of LanCL2 suppressed migration, invasion and invadopodia formation of glioblastoma cells, whereas overexpression of wild-type LanCL2 enhanced them. Blocking of Tyr295 residue phosphorylation of LanCL2 impeded its nuclear transport, retarded glioblastoma cell motility and invadopodia formation, and deceased the phosphorylation of Cortactin and STAT3. c-Met was identified as the upstream tyrosine kinase of Tyr295 residue of LanCL2, and inhibition of c-Met markedly suppressed the nuclear transport of LanCL2. Moreover, overexpression of wild-type LanCL2 significantly promoted orthotopic tumor growth of glioblastoma in vivo and led to poor survival of mice with median survival time of 33.5 days, whereas Tyr295 mutation rescued it with median survival time of 49 days.

Conclusion: Our findings suggested that Tyr295 phosphorylation is crucial to the activation and nuclear transport of LanCL2, as well as invadopodia formation and tumor progression of glioblastoma, providing the evidence of a novel signaling axis c-Met/LanCL2/STAT3/Cortactin and the first observation of the importance of Tyr295 phosphorylation to LanCL2.

Keywords: Glioblastoma; Invadopodia; LanCL2; Nuclear transport; Tumor progression.