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Published on: November 5, 2014
Claudin-4: A New Molecular Target for Epithelial Cancer Therapy
Rina Fujiwara-Tani1, Shiori Mori1, Ruiko Ogata1
1Department of Molecular Pathology, Nara Medical University, Kashihara 634-8521, Japan.
Abstract:
Claudin-4 (CLDN4) is a key component of tight junctions (TJs) in epithelial cells. CLDN4 is overexpressed in many epithelial malignancies and correlates with cancer progression. Changes in CLDN4 expression have been associated with epigenetic factors (such as hypomethylation of promoter DNA), inflammation associated with infection and cytokines, and growth factor signaling. CLDN4 helps to maintain the tumor microenvironment by forming TJs and acts as a barrier to the entry of anticancer drugs into tumors. Decreased expression of CLDN4 is a potential marker of epithelial-mesenchymal transition (EMT), and decreased epithelial differentiation due to reduced CLDN4 activity is involved in EMT induction. Non-TJ CLDN4 also activates integrin beta 1 and YAP to promote proliferation, EMT, and stemness. These roles in cancer have led to investigations of molecular therapies targeting CLDN4 using anti-CLDN4 extracellular domain antibodies, gene knockdown, clostridium perfringens enterotoxin (CPE), and C-terminus domain of CPE (C-CPE), which have demonstrated the experimental efficacy of this approach. CLDN4 is strongly involved in promoting malignant phenotypes in many epithelial cancers and is regarded as a promising molecular therapeutic target.
Insights
Claudin-4 (CLDN4) is overexpressed in epithelial cancers, promoting tumor growth and drug resistance. Targeting CLDN4 with molecular therapies shows promise for treating various malignancies.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Claudin-4 (CLDN4) is a crucial protein in epithelial tight junctions (TJs).
- CLDN4 overexpression is linked to epithelial cancer progression and influences the tumor microenvironment.
- CLDN4 expression changes are associated with epigenetic modifications, inflammation, and growth factor signaling.
Purpose of the Study:
- To investigate the multifaceted roles of Claudin-4 (CLDN4) in epithelial malignancies.
- To explore the potential of CLDN4 as a molecular therapeutic target in cancer treatment.
Main Methods:
- Review of literature on CLDN4 expression in various cancers.
- Analysis of CLDN4's involvement in tumor microenvironment modulation and drug resistance.
- Examination of CLDN4's non-tight junction functions in promoting cancer stemness and proliferation.
- Overview of emerging molecular therapies targeting CLDN4.
Main Results:
- CLDN4 overexpression correlates with cancer progression and acts as a barrier to anticancer drugs.
- Reduced CLDN4 expression is associated with epithelial-mesenchymal transition (EMT).
- Non-tight junction CLDN4 activates signaling pathways (integrin beta 1, YAP) promoting proliferation, EMT, and stemness.
- Experimental therapies targeting CLDN4, including antibodies and toxins, show efficacy.
Conclusions:
- Claudin-4 (CLDN4) plays a significant role in promoting malignant phenotypes across numerous epithelial cancers.
- CLDN4 is a promising molecular target for novel cancer therapies.
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