Claudin-3 facilitates the progression and mediates the tumorigenic effects of TGF-β in glioblastoma multiforme

Glioblastoma multiforme (GBM) is a significantly malignant and lethal brain tumor with an average survival time of less than 12 months. Several researches had shown that Claudin-3 (CLDN3) is overexpressed in various cancers and might be important in their growth and spread. In this study, we used qRT-PCR, western blotting, immunohistochemistry, and immunofluorescence staining assays to investigate the expression levels of various proteins. To explore the proliferation abilities of GBM cells, we conducted the CCK-8 and EdU-DNA formation assays. Wound healing and transwell assays were used to investigate the capacities of invasion and migration of GBM cells. Additionally, we constructed an intracranial xenograft model of GBM to study the in vivo role of CLDN3. Our study devoted to investigate the function of CLDN3 in the pathogenesis and progression of GBM. Our study revealed that CLDN3 was upregulated in GBM and could stimulate tumor cell growth and epithelial-mesenchymal transition (EMT) in both laboratory and animal models. We also discovered that CLDN3 expression could be triggered by transforming growth factor-β (TGF-β) and reduced by specific inhibitors of the TGF-β signaling pathway, such as ITD-1. Further analysis revealed that increased CLDN3 levels enhanced TGF-β-induced growth and EMT in GBM cells, while reducing CLDN3 levels weakened these effects. Our study demonstrated the function of CLDN3 in facilitating GBM growth and metastasis and indicated its involvement in the tumorigenic effects of TGF-β. Developing specific inhibitors of CLDN3 might, therefore, represent a promising new approach for treating this devastating disease.

 

Comments:

The study you described explores the role of Claudin-3 (CLDN3) in glioblastoma multiforme (GBM), a highly malignant brain tumor. The researchers used various techniques such as qRT-PCR, western blotting, immunohistochemistry, immunofluorescence staining, CCK-8 assay, EdU-DNA formation assay, wound healing assay, transwell assay, and an intracranial xenograft model to investigate the expression levels and functions of CLDN3 in GBM.

The key findings of the study are as follows:

1. **CLDN3 Overexpression in GBM:** The study found that CLDN3 was upregulated in GBM tissues, indicating its potential role in the pathogenesis and progression of the disease.

2. **Stimulating Tumor Cell Growth:** CLDN3 was shown to stimulate tumor cell growth in both laboratory and animal models, suggesting its involvement in the rapid proliferation of GBM cells.

3. **Promoting Epithelial-Mesenchymal Transition (EMT):** CLDN3 was found to promote EMT, a process where cells lose their epithelial characteristics and acquire mesenchymal properties, which is often associated with cancer metastasis.

4. **Regulation by TGF-β:** The study revealed that CLDN3 expression could be triggered by transforming growth factor-β (TGF-β), a signaling molecule known to play a role in cancer progression. Specific inhibitors of the TGF-β signaling pathway, such as ITD-1, reduced CLDN3 expression.

5. **Enhanced Effects of TGF-β:** Increased CLDN3 levels enhanced TGF-β-induced growth and EMT in GBM cells, suggesting a synergistic effect between CLDN3 and TGF-β in promoting tumor progression.

6. **Potential Therapeutic Implications:** The study concluded that developing specific inhibitors targeting CLDN3 might be a promising approach for treating GBM. By inhibiting CLDN3, researchers could potentially impede the growth and metastasis of GBM cells, offering a new avenue for therapeutic intervention in this devastating disease.

In summary, the study provides valuable insights into the molecular mechanisms underlying GBM progression, highlighting CLDN3 as a potential therapeutic target and paving the way for further research and drug development in the field of GBM treatment.

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S6713	ITD-1	ITD-1 is a potent TGF-β inhibitor. It does not block the kinase activity of either type I (TGFBR1) or type II (TGFBR2) TGFβ receptors but potently blocks phosphorylation of the effector SMAD2/3 proteins induced by TGFβ2, and only minimally in response to Activin A.

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TGF-beta/Smad