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GLI2 inhibits cisplatin sensitivity in gastric cancer through DEC1/ZEB1 mediated EMT
Wenshuai Zhu1, Jingguo Sun1, Fubo Jing2
1Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
Abstract:
Cisplatin (CDDP) based chemotherapy has emerged as the predominant therapeutic regimen for patients with advanced gastric cancer (GC). However, its efficacy is dampened by the development of chemoresistance, which results in poor prognosis of patients. GLI2, a key transcription factor in the Hedgehog (Hh) signaling pathway, is regarded as a target for cancer therapy. However, the significance of GLI2 for CDDP resistance in GC has not been well established. Here, we show that GLI2 expression was upregulated in EMT-type GC and associated with poor prognosis. GLI2 promotes proliferation, migration, and CDDP resistance of GC cells by inducing EMT. In terms of mechanism, GLI2 binds to the promoter region of DEC1 and enhances its expression, thereby co-transcriptionally regulating ZEB1 expression. Animal experiments have demonstrated that both GLI2 knockdown and GLI2 inhibitor significantly enhance CDDP sensitivity in GC. Our data not only identify a novel GLI2/DEC1/ZEB1/EMT pathway in GC CDDP resistance but also provide novel strategies to treat GC in the future.
Insights
This study reveals that GLI2 drives cisplatin resistance in gastric cancer (GC) by promoting epithelial-mesenchymal transition (EMT). Targeting GLI2 enhances chemotherapy sensitivity, offering new treatment strategies for advanced GC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cisplatin (CDDP) is a primary chemotherapy for advanced gastric cancer (GC).
- Chemoresistance to CDDP significantly limits treatment efficacy and patient prognosis.
- The Hedgehog (Hh) signaling pathway transcription factor GLI2 is a potential therapeutic target, but its role in CDDP resistance in GC is unclear.
Purpose of the Study:
- To investigate the role of GLI2 in CDDP resistance in gastric cancer.
- To elucidate the molecular mechanisms underlying GLI2-mediated chemoresistance.
- To evaluate GLI2 as a therapeutic target for overcoming CDDP resistance in GC.
Main Methods:
- Analysis of GLI2 expression in EMT-type GC tissues and correlation with prognosis.
- In vitro studies assessing GLI2's impact on GC cell proliferation, migration, and CDDP resistance.
- Mechanistic studies involving promoter binding assays and gene expression analysis (DEC1, ZEB1).
- In vivo experiments using animal models to evaluate the effect of GLI2 inhibition on CDDP sensitivity.
Main Results:
- GLI2 expression is upregulated in EMT-type GC and linked to poor prognosis.
- GLI2 promotes GC cell proliferation, migration, and CDDP resistance via EMT induction.
- GLI2 directly enhances DEC1 expression, co-transcriptionally regulating ZEB1.
- GLI2 knockdown and GLI2 inhibitors significantly improve CDDP sensitivity in GC models.
Conclusions:
- A novel GLI2/DEC1/ZEB1/EMT pathway contributes to CDDP resistance in gastric cancer.
- GLI2 is a critical mediator of chemoresistance and a potential therapeutic target for GC.
- Targeting GLI2 offers a promising strategy to enhance CDDP efficacy in treating advanced gastric cancer.
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