Cysteine‑ and glycine‑rich protein 2: A vital regulator that inhibits necroptosis glioma cell by activating the JAK‑STAT1 pathways.

in Oncology reports by Dongsheng Lv, Xu Han, Liang Hao, Zhimin Sun, Aobo Zhang, Jing Liu, Liang Liu, Liqiang Liu

TLDR

  • CSRP2 overexpression promotes glioma cell proliferation and metastasis by activating the JAK-STAT1 signaling pathway and inhibiting necroptosis.
  • Silencing of CSRP2 inhibits JAK-STAT1 activation and promotes necroptosis in glioma cells.
  • Targeting CSRP2 and the JAK-STAT1 signaling pathway may be a promising therapeutic approach for glioma treatment.

Abstract

Cysteine‑ and glycine‑rich protein 2 (CSRP2) are closely associated with tumor invasion and metastasis. CSRP2 is significantly upregulated in glioma tissues and is associated with the clinical stage of the tumor. Overexpression of CSRP2 in glioma cells promotes the proliferation and metastasis of cancer cells, whereas CSRP2 knockdown inhibits the biological functions of tumor cells. Transcriptome sequencing of CSRP2‑knockdown U251M cells revealed that silencing of CSRP2 inhibited the JAK‑STAT1 signaling pathway, and differentially expressed genes were significantly enriched in cell processes related to necroptosis. Experiments on necroptosis in glioma cells using flow cytometry, Hoechst 33342/PI dual staining and transmission electron microscopy indicated that CSRP2 overexpression inhibited necroptosis in glioma cells. Western blotting results showed that overexpression of CSRP2 activated the JAK‑STAT1 signaling pathway, while the addition of the pathway inhibitor ruxolitinib promoted the phosphorylation of necroptosis proteins RIPK1, RIPK3 and MLKL. Therefore, it was hypothesized that CSRP2 maintains JAK‑STAT1 activation by inhibiting the protein inhibitor of activated STAT1, which then inhibits the necrotizing apoptosis of glioma cells.

Overview

  • The study investigated the role of Cysteine- and glycine-rich protein 2 (CSRP2) in glioma tumorigenesis, focusing on its potential involvement in tumor invasion, metastasis, and necrotic cell death.
  • The researchers explored the molecular mechanisms underlying CSRP2's effects, specifically its interactions with the JAK-STAT1 signaling pathway and its impact on necroptosis in glioma cells.
  • The study aimed to elucidate how CSRP2 regulates the biological behaviors of glioma cells, shedding light on its potential as a therapeutic target for the treatment of glioma.

Comparative Analysis & Findings

  • CSRP2 overexpression in glioma cells promoted cell proliferation and metastasis, while its knockdown inhibited these biological processes.
  • The JAK-STAT1 signaling pathway was activated in CSRP2-overexpressing glioma cells, but was inhibited in CSRP2-knockdown cells.
  • Silencing of CSRP2 resulted in the downregulation of genes involved in necroptosis, indicating that CSRP2 inhibits necrotic cell death in glioma cells.

Implications and Future Directions

  • The study suggests that targeting CSRP2 and the JAK-STAT1 signaling pathway may be a promising therapeutic approach for glioma treatment.
  • Future studies could investigate the mechanisms underlying CSRP2's regulation of necroptosis and explore the use of CSRP2 as a biomarker for glioma diagnosis and prognosis.
  • The identification of CSRP2 as a key regulator of glioma biology provides new avenues for the development of targeted therapies and highlights the importance of understanding the molecular mechanisms underlying glioma tumorigenesis.
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