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

in Journal of advanced research by 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

TLDR

  • The study looked at how a protein called LanCL2 affects the growth and spread of a type of brain tumor called glioblastoma. The study found that LanCL2 plays a crucial role in the formation of structures called invadopodia, which help the tumor cells move and spread. The study also found that a specific part of LanCL2 called Tyr295 is important for the protein to work properly. The study provides evidence for a new way that the protein works and could help with the development of new treatments for glioblastoma.

Abstract

The abscisic acid receptor Lanthionine synthetase C-like 2 (LanCL2) is a prognostic factor for overall survival in young glioblastoma patients. However, the role and underlying mechanism of LanCL2 in glioblastoma remain unclear yet. This study is to investigate the role of LanCL2 in regulating in-vitro cell invasion and in-vivo tumor progression of glioblastoma and its underlying mechanism. Tyrosine 198 or 295 residue of LanCL2 was mutated using site-directed mutagenesis to block its phosphorylation. The roles of LanCL2 in glioblastoma were studied using transwell or 3D invasion assay, matrix degradation assay and intracranial xenograft model. This study showed the nuclear localization signals of LanCL2 and increased nuclear transport by abscisic acid or overexpression of LanCL2 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. 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 GBM, 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.

Overview

  • The study investigates the role of LanCL2 in regulating in-vitro cell invasion and in-vivo tumor progression of glioblastoma and its underlying mechanism. The study used site-directed mutagenesis to block the phosphorylation of LanCL2 at Tyr198 or 295 residue. The roles of LanCL2 in glioblastoma were studied using transwell or 3D invasion assay, matrix degradation assay, and intracranial xenograft model. The study showed that LanCL2 plays a crucial role in invadopodia formation and tumor progression of GBM, and that Tyr295 phosphorylation is crucial to the activation and nuclear transport of LanCL2. The study provides evidence of a novel signaling axis c-Met/LanCL2/STAT3/Cortactin and the first observation of the importance of Tyr295 phosphorylation to LanCL2.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions, including the effects of mutating LanCL2 at Tyr198 or 295 residue, overexpression of LanCL2, and inhibition of c-Met. The study identified significant differences in the results between these conditions, such as the suppression of migration, invasion, and invadopodia formation by knockdown of LanCL2, the enhancement of these processes by overexpression of wild-type LanCL2, and the suppression of these processes by inhibition of c-Met. The study also discussed the key findings of the study and how they relate to the initial hypothesis, such as the importance of Tyr295 phosphorylation to the activation and nuclear transport of LanCL2, and the role of c-Met in this process.

Implications and Future Directions

  • The study's findings have significant implications for the field of research or clinical practice, such as the identification of a novel signaling axis c-Met/LanCL2/STAT3/Cortactin and the importance of Tyr295 phosphorylation to LanCL2. The study also identified limitations of the study that need to be addressed in future research, such as the need to investigate the role of LanCL2 in other types of cancer. The study suggests possible future research directions that could build on the results of the study, explore unresolved questions, or utilize novel approaches, such as the development of targeted therapies that target c-Met or Tyr295 phosphorylation of LanCL2.
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