A Key Claudin Extracellular Loop Domain is Critical for Epithelial Barrier Integrity

Mrsny, Randall J.; Brown, G. Thomas; Gerner-Smidt, Kirsten; Buret, André G.; Meddings, Jon; Quan, Clifford; Koval, Michael; Nusrat, Asma

doi:10.2353/ajpath.2008.070698

Cited by 109 publications

(98 citation statements)

References 52 publications

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“…Finally, CLDN1 levels were regulated by β-catenin. CLDN1 is a member of tight junction protein which generally plays a role in maintaining the integrity of the barrier function in normal epithelial cells (34). However, in tumor cells, CLDN1 was discovered to be either a promoter or an inhibitor.…”

Section: Discussionmentioning

confidence: 99%

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

Huang

et al. 2014

International Journal of Oncology

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Abstract. Claudin 1 is one of the tight junction proteins, which are critical in the maintenance of epithelial integrity. Aberrant regulation of CLDN1 and its correlation with β-catenin have been discovered in malignant tumors. The present study aimed to investigate the expression profile and clinical relevance of CLDN1 and β-catenin. The protein levels of CLDN1 and β-catenin were examined using immunohistochemical staining. The characteristics of expression profile and prognostic value were analyzed using Pearson's χ 2 test and Kaplan-Meier analysis, respectively. β-catenin overexpression and knockdown were used to investigate its role in regulating CLDN1 expression. We showed that CLDN1 was overexpressed in intestinal-type, presence of lymph node metastasis, higher TNM stage in gastric cancer patients and correlated with decreased overall survival. The characteristics of CLDN1 expression were associated with that of β-catenin. CLDN1 and β-catenin showed similar prognostic value in intestinal-type gastric cancers. β-catenin knockdown and overexpression in cell models revealed a positive relation between CLDN1 and β-catenin. Our study demonstrated that CLDN1 is a biomarker for intestinal-type gastric cancer with shorter survival. The expression of CLDN1 was strongly associated with β-catenin in gastric cancer patients and a gastric cancer cell model. IntroductionGastric cancer is the fourth most common cancer worldwide and is the second most common cause of cancer-related deaths.Gastric cancer has a poor prognosis (1). Although the 5-year survival rate in patients with early-stage disease is ~90%, since the vast majority present with distant metastasis, the overall 5-year survival rate is typically <20% (2). The 5-year survival rate has also been significantly correlated with the degree of tumor invasion, the presence of lymph node and/ or distant metastases and the TNM stage (3,4). However, very limited number of molecules that have clinicopathological significance in gastric cancer has been discovered.Claudin 1 (CLDN1) is one of the integral membrane proteins that constitute tight junctions. Tight junctions are essential for the tight sealing of cellular sheets and maintaining homeostasis (5). Absence of tight junctions or defective tight junctions is associated with the development of the neoplastic phenotype in epithelial cells (6). Thus it is accepted that the disruption of tight junctions leads to loss of cohesion, invasiveness and the lack of differentiation, thereby promoting tumorigenesis. CLDN1 is found to regulate intestinal epithelial homeostasis through the modulation of Notch-signaling (7). Many chemicals and nutrition can regulate CLDN1 expression through different pathways (8,9) to maintain the integrity of intestinal barrier function.The complexity of CLDN1 was proposed because its dual role as a tumor suppressor and promoter, as well as a positive and negative prognostic factor in different cancers, including breast (10,11), gastric (12), ovarian (13), lung (14) and colon (15-17). Decreased exp...

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Section: Discussionmentioning

confidence: 99%

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

Huang

et al. 2014

International Journal of Oncology

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“…The most important of these tight junction proteins appear to be in the claudin family (84,85). Claudin-4 is expressed at high levels in both AT1 and AT2 cells (86).…”

Section: Wwwannualreviewsorg • Repair Of the Alveolar-capillary Barmentioning

confidence: 99%

Regulation and Repair of the Alveolar-Capillary Barrier in Acute Lung Injury

Bhattacharya

Matthay

2013

Annu. Rev. Physiol.

288

208

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Considerable progress has been made in understanding the basic mechanisms that regulate fluid and protein exchange across the endothelial and epithelial barriers of the lung under both normal and pathological conditions. Clinically relevant lung injury occurs most commonly from severe viral and bacterial infections, aspiration syndromes, and severe shock. The mechanisms of lung injury have been identified in both experimental and clinical studies. Recovery from lung injury requires the reestablishment of an intact endothelial barrier and a functional alveolar epithelial barrier capable of secreting surfactant and removing alveolar edema fluid. Repair mechanisms include the participation of endogenous progenitor cells in strategically located niches in the lung. Novel treatment strategies include the possibility of cell-based therapy that may reduce the severity of lung injury and enhance lung repair.

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“…[5][6][7][8][9][10][11] Foremost among these tight junction proteins is the claudin family. [12][13][14] In both types 1 and 2 pneumocytes, claudin-4 is expressed at high levels. 15 Previously reported loss of function studies showed that claudin 4 was required for maximal epithelial barrier function, including alveolar fluid clearance in mice.…”

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confidence: 99%

Claudin-4 Levels Are Associated with Intact Alveolar Fluid Clearance in Human Lungs

Rokkam

LaFemina

Lee

et al. 2011

The American Journal of Pathology

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A Key Claudin Extracellular Loop Domain is Critical for Epithelial Barrier Integrity

Cited by 109 publications

References 52 publications

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

The expression of Claudin 1 correlates with β-catenin and is a prognostic factor of poor outcome in gastric cancer

Regulation and Repair of the Alveolar-Capillary Barrier in Acute Lung Injury

Claudin-4 Levels Are Associated with Intact Alveolar Fluid Clearance in Human Lungs

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