The role of claudin-1 in the initiation and progression of hepatocellular carcinoma

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

During cancer progression, tight junctions behave as mechanical restraints by anchoring malignant cells to their neighbours thereby inhibiting the metastatic development of primary tumours. Tight junctions not only behave as cell-cell junctional barriers but active participants in cell signalling pathways regulating cell proliferation, polarity, and differentiation.

The increased and decreased expression of the tight junctional protein claudin-1 has been associated with higher tumour grades and lower survival rates in hepatocellular carcinoma. Despite these observations, little is known about how claudin-1 influences the molecular mechanisms involved in the initiation and progression of the disease. By overexpressing and silencing claudin-1 in the HepG2 hepatocellular carcinoma cell line, we have demonstrated that the aberrant expression of claudin-1 induces an invasive phenotype with increased migratory capacity that is consistent with the observational evidence published in the literature.

Overexpression of claudin-1 in the HepG2 cell line resulted in an increase in the mRNA levels of mesenchymal and tumour metastasis genes such as vimentin, MMP -2, -9 and 13, SNAIL, SLUG, TWIST, and ZEB1/2. Furthermore, a significant decrease in the mRNA levels of epithelial markers E-cadherin, cytokeratin-7, -14, -19 and miR-200a, b, c was also observed in these cells. Silencing of claudin-1 in HepG2 cells resulted in increased mRNA expression of vimentin, N-cadherin, MMP -2, -9, and -13, FOXC2, TWIST, and ZEB2. These cells also displayed increased mRNA levels of stem cell markers CD44, CK19, NOTCH, and JAGGED. The classical downregulation of epithelial markers combined with the upregulation of mesenchymal markers provide evidence that aberrant expression of claudin-1 induces EMT in these cells.
Date of Award22 Mar 2019
Original languageEnglish
Awarding Institution
  • Coventry University
SupervisorAfthab Hussain (Supervisor), Christopher Mee (Supervisor) & Elaine Green (Supervisor)

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