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Review
. 2015 Aug;3(13):184.
doi: 10.3978/j.issn.2305-5839.2015.08.01.

Paradigms lost-an emerging role for over-expression of tight junction adhesion proteins in cancer pathogenesis

Astrid O Leech  1 , Rodrigo G B Cruz  1 , Arnold D K Hill  1 , Ann M Hopkins  1
Affiliations
Review

Paradigms lost-an emerging role for over-expression of tight junction adhesion proteins in cancer pathogenesis

Astrid O Leech et al. Ann Transl Med. 2015 Aug.

Abstract

Tight junctions (TJ) are multi-protein complexes located at the apicalmost tip of the lateral membrane in polarised epithelial and endothelial cells. Their principal function is in mediating intercellular adhesion and polarity. Accordingly, it has long been a paradigm that loss of TJ proteins and consequent deficits in cell-cell adhesion are required for tumour cell dissemination in the early stages of the invasive/metastatic cascade. However it is becoming increasingly apparent that TJ proteins play important roles in not just adhesion but also intracellular signalling events, activation of which can contribute to, or even drive, tumour progression and metastasis. In this review, we shall therefore highlight cases wherein the gain of TJ proteins has been associated with signals promoting tumour progression. We will also discuss the potential of overexpressed TJ proteins to act as therapeutic targets in cancer treatment. The overall purpose of this review is not to disprove the fact that loss of TJ-based adhesion contributes to the progression of several cancers, but rather to introduce the growing body of evidence that gain of TJ proteins may have adhesion-independent consequences for promoting progression in other cancers.

Keywords: Cancer; HER2; adhesion; claudin; coxsackievirus and adenovirus receptor (CAR); junctional adhesion molecule A (JAM-A); metastasis; over-expression; tight junction (TJ); tumorigenesis; zonula occludens (ZO) proteins.

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Conflict of interest statement

Conflicts of Interest: The authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Mechanisms by which JAM-A may promote tumorigenesis. (A) JAM-A dimerization leads to Rap1 activation and subsequent upregulation of β1-integrin, enhancing cell migration; (B) JAM-A overexpression promotes cancer stem cell (CSC) self-renewal in triple-negative breast cancer; (C) JAM-A induces epithelial to mesenchymal transition (EMT) in nasopharyngeal carcinoma cells via the PI3K and MAPK pathways; (D) JAM-A stabilises HER2 expression in breast cancer cells by putatively inhibiting HER2 proteasomal degradation, promoting signalling via the PI3K and MAPK pathways which results in cellular proliferation and the inhibition of apoptosis. Many of the arrows depict processes that require several steps.
See this image and copyright information in PMC

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