Tight Junction Proteins as Therapeutic Targets to Treat Liver Fibrosis and Hepatocellular Carcinoma

Saviano, Antonio; Roehlen, Natascha; Baumert, Thomas F.

doi:10.1055/s-0044-1785646

Semin Liver Dis

2024

DOI: 10.1055/s-0044-1785646

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Tight Junction Proteins as Therapeutic Targets to Treat Liver Fibrosis and Hepatocellular Carcinoma

Antonio Saviano,

Natascha Roehlen,

Thomas F. Baumert

Abstract: In the last decade tight junction proteins exposed at the surface of liver or cancer cells have been uncovered as mediators of liver disease biology: Claudin-1 and Occludin are host factors for hepatitis C virus entry and Claudin-1 has been identified as a driver for liver fibrosis and hepatocellular carcinoma (HCC). Moreover, Claudins have emerged as therapeutic targets for liver disease and HCC. CLDN1 expression is upregulated in liver fibrosis and HCC. Monoclonal antibodies (mAbs) targeting Claudin-1 have c… Show more

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Cited by 3 publications

References 108 publications

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Biomimetic Topological Micropattern Arrays Regulate the Heterogeneity of Cellular Fates in Lung Fibroblasts between Fibrosis and Invasion

Zhu,

Mao,

Yang

et al. 2025

ACS Nano

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Biomimetic Topological Micropattern Arrays Regulate the Heterogeneity of Cellular Fates in Lung Fibroblasts between Fibrosis and Invasion

Zhu,

Mao,

Yang

et al. 2025

ACS Nano

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Exploring the Critical Role of Tight Junction Proteins in Kidney Disease Pathogenesis

Jayne,

Herbert,

Anquetil

et al. 2024

Nephron

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Background: Kidney disease poses a significant global health challenge, marked by a rapid decline in renal function due to a variety of causative factors. A crucial element in the pathophysiology of kidney disease is the dysregulation of epithelial cells, which are vital components of renal tissue architecture. The integrity and functionality of these cells are largely dependent on tight junctions (TJ) proteins, complex molecular structures that link adjacent epithelial cells. These TJ not only confer cellular polarity and maintain essential barrier functions but also regulate epithelial permeability. Summary: TJ proteins are pivotal in their traditional role at cell junctions and in their non-junctional capacities. Recent research has shifted the perception of these proteins from mere structural elements to dynamic mediators of kidney disease, playing significant roles in various renal pathologies. This review explores the multifaceted roles of TJ proteins, focusing on their functions both within and external to the renal epithelial junctions. It highlights how these proteins contribute to mechanisms underlying kidney disease, emphasizing their impact on disease progression and outcomes. Key Messages: TJ proteins have emerged as significant players in the field of nephrology, not only for their structural role but also for their regulatory functions in disease pathology. Their dual roles in maintaining epithelial integrity and mediating pathological processes make them promising therapeutic targets for kidney disease. Understanding the intricate contributions of TJ proteins in kidney pathology offers potential for novel therapeutic strategies, aiming to modulate these proteins to halt or reverse the progression of kidney disease.

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Peripheral immune signatures associated with the risk of hepatocarcinogenesis in cirrhotic Egyptian HCV patients before and after treatment with direct-acting antivirals

El-Shenawy,

Moustafa,

Helmy

et al. 2024

Virol J

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Background Although direct-acting antivirals (DAAs) have revolutionized the management of chronic HCV, the debatable association with hepatocellular carcinoma (HCC) occurrence/recurrence has raised major concerns about their long-term use, especially in cirrhotic cases. The role of epithelial tight junction proteins (TJPs) in hepatocarcinogenesis has been highlighted; however, the association of their expression in peripheral blood mononuclear cells (PBMCs) with HCC has rarely been reported. This study aimed to explore the role of peripheral claudin (Cldn)1 in liver pathogenesis and its crosstalk with soluble immune mediators in HCC prognosis. Methods The study population included six independent subgroups: healthy controls, cirrhotic/non-cirrhotic treatment-naïve HCV patients, DAA-SVR patients, and anticancer treatment-naïve de novo HCC patients. The laboratory tests included serum levels of alpha-fetoprotein (AFP), albumin, liver transaminases, total bilirubin, and CBC profiling. The serum levels of soluble cluster of differentiation (sCD)163, IL-10, and IL-12 were estimated by corresponding ELISA kits, whereas the levels of Cldn1 and transforming growth factor (TGF)-β in PBMCs were quantified using quantitative PCR (qPCR). Results Serum sCD163, IL-10, and IL-12 levels were significantly higher in the HCC patient group than in the control and non-malignant patient groups (P < 0.0001). No significant difference was detected in the serum levels of the three markers between cirrhotic and non-cirrhotic patients, whereas their levels were significantly different between cirrhotic and non-cirrhotic patients (P < 0.0001). Similarly, the transcriptional levels of peripheral Cldn1 and TGF-β were significantly higher in patients with HCC and non-malignant cirrhosis than in patients without cirrhosis (P = 0.0185–<0.0001 and 0.0089–<0.0001, respectively). Logistic regression analysis revealed a significant association between all the abovementioned markers and HCC (P = 0.0303 to < 0.0001), which was further confirmed by the results of receiver operating characteristic (ROC) analysis, which revealed an area under the curve (AUC) value ranging from 0.883 to 0.996. The calculated cutoff values demonstrated remarkable prognostic capacity, with ranges of 88–99.41% and 82.14–97.92% and positive/negative predictive values ranging from 84.62 to 98.3% and 92–98%, respectively. Conclusion The proposed HCC predictors are novel non-invasive HCC biomarkers that maintain their predictive power under different pathological conditions and circumvent the drawbacks of conventional prognostic markers in patients with mild cirrhosis and/or normal AFP, albumin, and/or platelet counts.

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Tight Junction Proteins as Therapeutic Targets to Treat Liver Fibrosis and Hepatocellular Carcinoma

Cited by 3 publications

References 108 publications

Biomimetic Topological Micropattern Arrays Regulate the Heterogeneity of Cellular Fates in Lung Fibroblasts between Fibrosis and Invasion

Biomimetic Topological Micropattern Arrays Regulate the Heterogeneity of Cellular Fates in Lung Fibroblasts between Fibrosis and Invasion

Exploring the Critical Role of Tight Junction Proteins in Kidney Disease Pathogenesis

Peripheral immune signatures associated with the risk of hepatocarcinogenesis in cirrhotic Egyptian HCV patients before and after treatment with direct-acting antivirals

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