The keratins and their disorders

Rugg, Elizabeth L.; Leigh, Irene M.

doi:10.1002/ajmg.c.30029

Cited by 50 publications

(38 citation statements)

References 71 publications

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“…Cytokeratins form the intermediate filaments of the cytokeleton in epithelial cells. There are multiple so-called acidic and basic cytokeratins, and these form specific dimers that aggregate into filaments (48,49). Interestingly, keratin 4 and 13 are such a dimer, supporting the validity of our findings.…”

Section: Discussionsupporting

confidence: 86%

Differential Proteomics Identifies Protein Biomarkers That Predict Local Relapse of Head and Neck Squamous Cell Carcinomas

Schaaij-Visser

Graveland

Gauci

et al. 2009

Clinical Cancer Research

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Purpose: The 5-year survival rates of head and neck squamous cell carcinomas (HNSCC) remain disappointing. HNSCCs develop in precursor fields of genetically altered cells that are often not completely resected when the tumor is excised, causing local relapse. These precursor fields are mostly recognized as dysplasia, but histologic grading cannot reliably predict malignant transformation. Our aim was to discover and validate protein biomarkers that can detect precursor fields and predict local relapse in HNSCC using immunostaining of surgical margins. Experimental Design: We compared paired and genetically characterized normal, precursor, and tumor tissues of eight patients by proteome analysis to identify differentially expressed proteins. The prognostic value of candidate protein biomarkers was evaluated by immunohistochemical analysis of 222 surgical margins of 46 HNSCC patients who developed local relapse or remained disease free. Significant associations were determined by Kaplan-Meier survival analysis and Cox-proportional hazards models. Results: Forty proteins showed significant differential expression (false discovery ratecorrected P < 0.05). Most discriminative markers suited for immunostaining were keratin 4 and cornulin. Low expression in the surgical margins of keratin 4 (hazard ratio, 3.8; P = 0.002), cornulin (hazard ratio, 2.7; P = 0.025), and their combination (hazard ratio, 8.8; P = 0.0005) showed a highly significant association with the development of local relapse. Dysplasia grading had no prognostic relevance. Conclusions: Immunohistochemical assessment of keratin 4 and cornulin expression in surgical margins of HNSCC patients outperforms histopathologic grading in predicting the risk for local relapse. These markers can be used to initiate more frequent and lifelong surveillance of patients at high risk of local relapse, and enable selection for adjuvant treatment or tertiary prevention trials. (Clin Cancer Res 2009;15(24):7666-75) Head and neck squamous cell carcinoma (HNSCC) develops in the mucosal linings of the upper aerodigestive tract and is the sixth most common cancer worldwide (1). The 5-year survival rates of HNSCC are approximately 60% (1) and have only moderately improved the last decades (2) mainly because 20% to 40% of all patients develop a local relapse in the same or adjacent anatomic region even when the surgical margins are histologically tumor free (3, 4). Clinically these relapses at the primary and adjacent anatomic sites are assigned as local recurrences when they develop within three years and at <2 cm distance of the primary tumor. Relapses not fulfilling these criteria are clinically classified as second primary tumors. Despite the difference in clinical assignment, many local relapses have in fact the same pathobiological origin (3-8).It has been well established that HNSCC is the result of a multistep process characterized by the accumulation of genetic and epigenetic alterations (9). Genetic analysis of surgical margins has shown that HNSCC frequent...

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Section: Discussionsupporting

confidence: 86%

Differential Proteomics Identifies Protein Biomarkers That Predict Local Relapse of Head and Neck Squamous Cell Carcinomas

Schaaij-Visser

Graveland

Gauci

et al. 2009

Clinical Cancer Research

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“…Histological analyses revealed that K5.Smad2 -/-tumors were generally poorly differentiated. The earliest K5.Smad2 -/-papillomas lacked stratified epithelial structure ( Figure 2C) and exhibited loss of loricrin and filaggrin, which are terminal differentiation markers (data not shown), and K1, an early differentiation marker ( Figure 2C), but expressed K8 ( Figure 2C), a marker of simple epithelia that is not expressed in stratified epithelia but is usually expressed in late-stage SCCs (20). In contrast, papillomas in WT mice showed partial or complete loss of loricrin and filaggrin (data not shown), without K8 expression, but retained uniform K1 expression (Figure 2C).…”

Section: Resultsmentioning

confidence: 96%

Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression

et al. 2008

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TGF-β and its signaling mediators, Smad2, -3, and -4, are involved with tumor suppression and promotion functions. Smad4 -/-mouse epidermis develops spontaneous skin squamous cell carcinomas (SCCs), and Smad3 -/-mice are resistant to carcinogen-induced skin cancer; however, the role of Smad2 in skin carcinogenesis has not been explored. In the present study, we found that Smad2 and Smad4, but not Smad3, were frequently lost in human SCCs. Mice with keratinocyte-specific Smad2 deletion exhibited accelerated formation and malignant progression of chemically induced skin tumors compared with WT mice. Consistent with the loss of Smad2 in poorly differentiated human SCCs, Smad2 -/-tumors were poorly differentiated and underwent epithelial-mesenchymal transition (EMT) prior to spontaneous Smad4 loss. Reduced E-cadherin and activation of its transcriptional repressor Snail were also found in Smad2 -/-mouse epidermis and occurred more frequently in Smad2-negative human SCCs than in Smad2-positive SCCs. Knocking down Snail abrogated Smad2 loss-associated EMT, suggesting that Snail upregulation is a major mediator of Smad2 loss-associated EMT. Furthermore, Smad2 loss led to a significant increase in Smad4 binding to the Snail promoter, and knocking down either Smad3 or Smad4 in keratinocytes abrogated Smad2 loss-associated Snail overexpression. Our data suggest that enhanced Smad3/Smad4-mediated Snail transcription contributed to Smad2 loss-associated EMT during skin carcinogenesis.

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“…[21][22][23][24][25][26] In normal human epidermis, heterodimers of keratin 5 (K5) and K14 form the cytoskeleton of undifferentiated cells in the basal layer, which is replaced in suprabasal cells by K1 and K10, accompanied by K2 in the review review and KRT17. [28][29][30] Upon differentiation of keratinocytes, e.g., by raising the calcium level with or without the addition of growth factors (EGF and fibroblast growth factor-10) or adding the EGF-receptor inhibitor PD153035, expression of the differentiation-related keratins K1 and K10 are induced in a subpopulation of cells.…”

Section: Keratin Expression In Normal Human Skin and Cultured Keratinmentioning

confidence: 99%

Regulation of keratin expression by retinoids

Törmä

2011

Dermato-Endocrinology

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The keratins and their disorders

Cited by 50 publications

References 71 publications

Differential Proteomics Identifies Protein Biomarkers That Predict Local Relapse of Head and Neck Squamous Cell Carcinomas

Differential Proteomics Identifies Protein Biomarkers That Predict Local Relapse of Head and Neck Squamous Cell Carcinomas

Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression

Regulation of keratin expression by retinoids

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