TGF-β induces GBM mesenchymal transition through upregulation of CLDN4 and nuclear translocation to activate TNF-α/NF-κB signal pathway

Abstract

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. The unregulated expression of Claudin-4 (CLDN4) plays an important role in tumor progression. However, the biological role of CLDN4 in GBM is still unknown. This study aimed to determine whether CLDN4 mediates glioma malignant progression, if so, it would further explore the molecular mechanisms of carcinogenesis. Our results revealed that CLDN4 was significantly upregulated in glioma specimens and cells. The inhibition of CLND4 expression could inhibit mesenchymal transformation, cell invasion, cell migration and tumor growth in vitro and in vivo. Moreover, combined with in vitro analysis, we found that CLDN4 can modulate tumor necrosis factor-α (TNF-α) signal pathway. Meanwhile, we also validated that the transforming growth factor-β (TGF-β) signal pathway can upregulate the expression of CLDN4, and promote the invasion ability of GBM cells. Conversely, TGF-β signal pathway inhibitor ITD-1 can downregulate the expression of CLDN4, and inhibit the invasion ability of GBM cells. Furthermore, we found that TGF-β can promote the nuclear translocation of CLDN4. In summary, our findings indicated that the TGF-β/CLDN4/TNF-α/NF-κB signal axis plays a key role in the biological progression of glioma. Disrupting the function of this signal axis may represent a new treatment strategy for patients with GBM.

The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway

“…RREB1 has been observed to act as an essential partner in the induction of EMT by the TGF-β1 pathway in tumors [30]. Increasing evidences show that TGF-β1 pathway was activated to promote the biological progression of glioma [47,48]. We further explored the correlation between RREB1 and TGF-β1 signaling pathway related signatures, and confirmed that the HALLMARK_TGF_BETA_SIGNALING signature enriched in higher RREB1 group.…”

<i>SERPINE1</i> as an Independent Prognostic Marker and Therapeutic Target for Nicotine-Related Oral Carcinoma

“…For instance, IL-17 promotes tumorigenesis by regulating beclin-1 ubiquitination [ 27 ]. The TNF signaling pathway mediates the mesenchymal transition of glioblastoma and plays a key role in its progression [ 28 ]. The data showed that several signaling pathways with different functions might be involved in the occurrence and development of nicotine-related oral cancer.…”

Integrated single-cell transcriptomic analyses reveal that GPNMB-high macrophages promote PN-MES transition and impede T cell activation in GBM

“…Furthermore, coupled with modeling intercellular crosstalk by NicheNet method, we investigated potential ligand-receptor-target interactions between tumor and non-tumor cells. Our unbiased analysis uncovered some interesting ligands, such as TGFB1, a master inducer in the mesenchymal transition, 59,60 which can promote the majority of our curative targets. LGALS3, produced by a variety of different cells, including macrophages, and endothelial cells, acts as another major source of this transcriptome change.…”