Down‐regulation of keratin 4 and keratin 13 expression in oral squamous cell carcinoma and epithelial dysplasia: a clue for histopathogenesis
Kei SakamotoTadanobu AragakiKeiichi MoritaHiroshi KawachiKou KayamoriShoichi NakanishiKen OmuraYoshio MikiNorihiko OkadaKen‐ichi KatsubeToichiro TakizawaAkira Yamaguchi
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Sakamoto K, Aragaki T, Morita K‐i, Kawachi H, Kayamori K, Nakanishi S, Omura K, Miki Y, Okada N, Katsube K‐i, Takizawa T & Yamaguchi A (2011) Histopathology 58, 531–542 Down‐regulation of keratin 4 and keratin 13 expression in oral squamous cell carcinoma and epithelial dysplasia: a clue for histopathogenesis Aims: This study aimed to identify relevant keratin subtypes that may associate with the pathogenesis of oral epithelial neoplasms. Methods and results: Expression of all the keratin subtypes was examined by cDNA microarray analysis of 43 oral squamous cell carcinoma (OSCC) cases. Immunohistochemical expression of the major keratins was examined in 100 OSCC and oral epithelial dysplasia (OED) cases. Many changes in keratin expression were observed and, significantly, consistent down‐regulation of keratin 4 (K4) and K13 expression was observed. Aberrant expression of K4 and K13 was associated with morphological changes in the affected oral epithelium. Experiments with cell cultures transfected with various keratin subtypes suggested that alterations in keratin subtype expression can cause changes in cell shape and movement. Conclusions: Aberrant expression of K4 and K13, which are the dominant pair of differentiation‐related keratins in oral keratinocytes, indicates dysregulation of epithelial differentiation in OSCC and OED. These keratins, especially K4, may be useful for pathological diagnosis. We propose that the aberrant expression of K4 and K13 and concomitant up‐regulation of the other keratins may be one of the causative factors for morphological alterations in the affected epithelium.Keywords:
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The importance of keratins and other intermediate filaments in the maintenance of tissue structure is emphasized by the discovery that many hereditary skin-blistering diseases are caused by mutations in keratin genes. Here, we describe a situation in which keratin 14 (K14) is missing altogether in the epidermis: A homozygous 2-nucleotide deletion in exon I of the K14 gene causes premature termination of the mRNA transcripts upstream from the start of the rod domain and results in a K14 null phenotype. In this individual no keratin intermediate filaments are visible in basal epidermal cells, although filaments are present in the upper layers of the epidermis. No compensating keratin expression is detected in vivo, and K14 mRNA is down-regulated. The individual, diagnosed as Köbner (generalized) EBS, suffers from severe widespread keratinocyte fragility and blistering at many body sites, but although the phenotype is severe, it is not lethal. This K14-/- phenotype confirms that only one K14 gene is expressed in human epidermis and provides an important model system for examining the interdependence of different keratin filament systems and their associated structures in the skin.
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Sakamoto K, Aragaki T, Morita K‐i, Kawachi H, Kayamori K, Nakanishi S, Omura K, Miki Y, Okada N, Katsube K‐i, Takizawa T & Yamaguchi A (2011) Histopathology 58, 531–542 Down‐regulation of keratin 4 and keratin 13 expression in oral squamous cell carcinoma and epithelial dysplasia: a clue for histopathogenesis Aims: This study aimed to identify relevant keratin subtypes that may associate with the pathogenesis of oral epithelial neoplasms. Methods and results: Expression of all the keratin subtypes was examined by cDNA microarray analysis of 43 oral squamous cell carcinoma (OSCC) cases. Immunohistochemical expression of the major keratins was examined in 100 OSCC and oral epithelial dysplasia (OED) cases. Many changes in keratin expression were observed and, significantly, consistent down‐regulation of keratin 4 (K4) and K13 expression was observed. Aberrant expression of K4 and K13 was associated with morphological changes in the affected oral epithelium. Experiments with cell cultures transfected with various keratin subtypes suggested that alterations in keratin subtype expression can cause changes in cell shape and movement. Conclusions: Aberrant expression of K4 and K13, which are the dominant pair of differentiation‐related keratins in oral keratinocytes, indicates dysregulation of epithelial differentiation in OSCC and OED. These keratins, especially K4, may be useful for pathological diagnosis. We propose that the aberrant expression of K4 and K13 and concomitant up‐regulation of the other keratins may be one of the causative factors for morphological alterations in the affected epithelium.
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The epidermal keratinocytes express two major pairs of keratin polypeptides. One pair (K5/K14) expressed specifically in basal generative compartment and the other (K1/K10) expressed specifically in the differentiating suprabasal compartment. The switch in the expression of the keratins from proliferating to differentiating compartment indicates the changes that occur in the keratin filament organization which in turn influences the functional properties of the epidermis. Proper regulation of keratin gene expression and the filament organization are absolutely necessary for normal functioning of the skin. Keratin gene mutations can influence the filament integrity thereby causing several heritable blistering disorders of the skin such as epidermolysis bullosa, bullous icthyosiform erythroderma, etc. Changes in the keratin gene expression may lead to incomplete differentiation of the epidermal keratinocyte, causing hyperproliferative diseases of the skin such as psoriasis, carcinomas, etc. This review briefly describes the changes in keratin structure or gene expression that are known to result in various disorders of the skin.
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Keratin expression in human tissues and neoplasms Keratin filaments constitute type I and type II intermediate filaments (IFs), with at least 20 subtypes named keratin 1–20. Since certain keratin subtypes are only expressed in some normal human tissues but not others, and vice versa , various tissues have been subclassified according to the pattern of keratin staining. Simple epithelia generally express the simple epithelial keratins 7, 18, 19, and 20, while complex epithelia express complex epithelial keratins 5/6, 10, 14, and 15. When an epithelium undergoes malignant transformation, its keratin profile usually remains constant. The constitution and expression patterns of keratin filaments in human epithelial neoplasms are complex and often distinctive. In this article, we first briefly review the molecular and cell biology of keratin filaments. We then focus on the expression patterns of keratin filaments in various human neoplasms.
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We investigate the keratin phenotype of human transitional epithelium at various gestational ages and whether keratin composition of transitional epithelium is related to bladder function and morphology.Consecutive sections from formalin fixed paraffin embedded blocks of autopsy bladder tissue from 21 male and 5 female fetuses, gestational age 12 to 40 weeks and 7 infants 2 days to 19 months old were cut and stained with antibodies recognizing basal cell keratins 5, 14 and 17, intermediate squamous cell keratin 13 and columnar cell keratins 7, 8, 18 and 20.With gestational age there were distinct changes in expression of keratins recognizing columnar cells, consisting of focal loss of keratin 7 in transitional epithelium, restriction of keratin 20 expression to umbrella cells and expression of keratin 18 throughout the full thickness of transitional epithelium. Basal cell keratin 5 was found above the basal cell layer while keratins 14 and 17 were not found. Squamous cell keratin 13 was found throughout the full thickness of the urothelium.The changes with gestational age in expression of some keratins may be related to the development of the reservoir function of the bladder. The impermeability of transitional epithelium, particularly during early fetal development, is possibly a function of umbrella and intermediate transitional cells.
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No AccessJournal of UrologyPEDIATRIC UROLOGY: Classic Article in Pediatric Urology1 Aug 2002Changing Patterns of Keratin Expression could be Associated with Functional Maturation of the Developing Human Bladder Jean de la rosette, Frank Smedts, Coen Schoots, Hans Hoek, and Pilar Laguna Jean de la rosetteJean de la rosette , Frank SmedtsFrank Smedts , Coen SchootsCoen Schoots , Hans HoekHans Hoek , and Pilar LagunaPilar Laguna View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)64731-3AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We investigate the keratin phenotype of human transitional epithelium at various gestational ages and whether keratin composition of transitional epithelium is related to bladder function and morphology. Materials and Methods: Consecutive sections from formalin fixed paraffin embedded blocks of autopsy bladder tissue from 21 male and 5 female fetuses, gestational age 12 to 40 weeks and 7 infants 2 days to 19 months old were cut and stained with antibodies recognizing basal cell keratins 5, 14 and 17, intermediate squamous cell keratin 13 and columnar cell keratins 7, 8, 18 and 20. Results: With gestational age there were distinct changes in expression of keratins recognizing columnar cells, consisting of focal loss of keratin 7 in transitional epithelium, restriction of keratin 20 expression to umbrella cells and expression of keratin 18 throughout the full thickness of transitional epithelium. Basal cell keratin 5 was found above the basal cell layer while keratins 14 and 17 were not found. Squamous cell keratin 13 was found throughout the full thickness of the urothelium. Conclusions: The changes with gestational age in expression of some keratins may be related to the development of the reservoir function of the bladder. The impermeability of transitional epithelium, particularly during early fetal development, is possibly a function of umbrella and intermediate transitional cells. References 1 : The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell1982; 31: 11. Crossref, Medline, Google Scholar 2 : Cytokeratine 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol1992; 140: 427. Google Scholar 3 : Keratins as differentiation markers in tumor biology and surgical pathology. In: Current Perspectives on Molecular and Cellular Oncology. Edited by . London: JAI Press1992: 285. Google Scholar 4 : Distribution of cytokeratin polypeptides in epithelia of the adult human urinary tract. Histochemistry1989; 91: 151. 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Link, Google Scholar 17 : The fine structure of the human fetal urinary bladder. Development and maturation. A light, transmission and scanning electron microscopic study. J Anat1989; 166: 135. Google Scholar 18 : Detection of keratin subtypes in routinely processed cervical tissue: implications for tumour classification and the study of cervix cancer etiology. Virchows Arch1994; 425: 145. Google Scholar 19 : Mammalian uroplakins. A group of highly conserved urothelial differentiation-related membrane proteins. J Biol Chem1994; 269: 13716. Crossref, Medline, Google Scholar 20 : The development of the human prostate gland with reference to the development of other structures at the neck of the urinary bladder. Am J Anat1901; 13: 299. Google Scholar 21 : Usefulness of immunoperoxidase staining with high-molecular-weight cytokeratin in the differential diagnosis of small-acinar lesions of the prostate gland. Virchows Arch A Pathol Anat Histopathol1990; 417: 191. 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Google Scholar From the Department of Urology, University Medical Center, St. Radboud Hospital, Nijmegen and the *Department of Pathology, Foundation of Collaborating Hospitals of Eastern Groningen, Groningen, The Netherlands© 2002 by American Urological Association, Inc.FiguresReferencesRelatedDetails Volume 168Issue 2August 2002Page: 709-717 Advertisement Copyright & Permissions© 2002 by American Urological Association, Inc.Keywordscell differentiationkeratinembryologyintermediate filamentsMetrics Author Information Jean de la rosette More articles by this author Frank Smedts More articles by this author Coen Schoots More articles by this author Hans Hoek More articles by this author Pilar Laguna More articles by this author Expand All Advertisement PDF downloadLoading ...
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