Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact

Singh, Amar B.; Dhawan, Punita

doi:10.1016/j.semcdb.2015.05.001

Cited by 61 publications

(51 citation statements)

References 98 publications

(121 reference statements)

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“…Claudin expression is frequently altered in cancer (18,66,67), with variable up-and downregulation depending on tissue type and disease stage (15,18,(68)(69)(70). There is thus no unifying concept as to how claudin dysregulation contributes mechanistically to carcinogenesis.…”

Section: Cldn18mentioning

confidence: 99%

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Zhou¹,

Flodby²,

Luo³

et al. 2018

Journal of Clinical Investigation

125

116

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Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18 -/-AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18 -/-mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.

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Section: Cldn18mentioning

confidence: 99%

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Zhou¹,

Flodby²,

Luo³

et al. 2018

Journal of Clinical Investigation

125

116

View full text Add to dashboard Cite

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“…Claudins are cell adhesion molecules and components of the tight junction complex, which regulate permeability between cells and maintain cell-cell integrity (15,16), and their role in carcinogenesis and progression to metastasis currently constitutes an active research focus (17). Claudins are known to act as barriers for the diffusion of solutes between epithelial cells, participating in the regulation of water transportation, ions and certain macromolecules.…”

Section: Introductionmentioning

confidence: 99%

“…The ‘claudin-low’ subtype of breast cancer is characterized by the reduced expression of claudin mRNAs, mainly claudins 3, 4 and 7 (11,12,14,20). Claudin expression deregulation has been previously implicated in cancer and is associated with metastasis and cancer progression (15,17), and low expression of claudins has been correlated to worse prognosis in breast cancer when assessed by RNA-based tests (14,17). …”

Section: Introductionmentioning

confidence: 99%

Immunoexpression of claudins 4 and 7 among invasive breast carcinoma subtypes: A large diagnostic study using tissue microarray

et al. 2018

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Molecular phenotyping and tissue microarray (TMA) studies have identified distinct invasive breast carcinoma subtypes: Luminal A, luminal B, enriched with overexpressed human epidermal growth factor receptor 2 (HER-2) and triple-negative, i.e., negative for HER-2, as well as for estrogen and progesterone receptor (ER and PR, respectively) expression. These subtypes are useful in clinical management, since they bear distinct prognoses and predictive responses to targeted therapy. However, although molecular profiling provides important prognostic indicators, breast cancer risk stratification remains a challenge in triple-negative cases. What is referred to as claudin-low subtype was identified as a triple-negative subset that is associated with more aggressive tumor behavior and worse prognosis. However, the immunohistochemical expression of claudins has not yet been standardized. Our objective was to verify whether the immunoexpression of claudins 4 and 7 (the main claudins specifically expressed in human breast tissue) in TMA is associated with survival and prognosis in luminal A, HER-2 and triple-negative molecular subtypes. In this diagnostic study, we investigated ER/PR receptor status, HER-2, claudin 4 and 7 expression and stem cell CD44/24 profiles, and verified the association with prognosis and survival outcomes in 803 invasive breast carcinoma cases arranged in four TMAs. Among these, 503 (62.6%) were positive for claudin 4 and 369 (46.0%) for claudin 7. Claudin 4 exhibited the lowest expression in luminal A and triple-negative subtypes, and the highest frequency of expression in HER-2-enriched subtypes, whereas claudin 7 staining was not associated with any subtype. The stem cell phenotype was not associated with subgroups or claudins 4 and 7. Claudin immunoexpression profile was not able to distinguish between patients with better or worse prognosis, and it was not correlated to triple-negative cases. Therefore, it may be concluded that the immunoexpression of claudins 4 and 7, individually or within the usual immunohistochemical context (ER, PR and HER-2), does not provide additional prognostic information on breast cancer subtypes.

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“…Loss of tight junction integrity seems to play a role in tumourigenesis of solid tumours 20. Depending on the type of neoplasia, claudin proteins may be reduced, elevated or mislocated in tumour cells compared with normal adjacent cells 21.…”

Section: Introductionmentioning

confidence: 99%

Claudin-1 is linked to presence of implants and micropapillary pattern in serous borderline epithelial tumours of the ovary

et al. 2018

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Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact

Cited by 61 publications

References 98 publications

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Immunoexpression of claudins 4 and 7 among invasive breast carcinoma subtypes: A large diagnostic study using tissue microarray

Claudin-1 is linked to presence of implants and micropapillary pattern in serous borderline epithelial tumours of the ovary

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