Expression of Simple Epithelial Keratins 8 and 18 in Epidermal Neoplasia

Markey, Andrew C.; Lane, E.B.; Churchill, Linda J.; Macdonald, D.M.; Leigh, Irene M.

doi:10.1111/1523-1747.ep12486607

Cited by 97 publications

(76 citation statements)

References 53 publications

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“…It has also been reported that K8/K18 are induced by v-ras in transformed epidermal keratinocytes (52,53) and that there is a positive correlation between the expression of these keratins and epidermal cell malignancy both in vitro (54) and in vivo (12,13). In transitional cell carcinoma, increased K8 and K18 levels have been detected at the tumor invasion front, and there is a relationship between the expression of these keratins and tumor malignancy (14,15).…”

Section: Discussionmentioning

confidence: 92%

Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8

Casanova¹,

Bravo²,

Ramı́rez³

et al. 1999

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 92%

Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8

Casanova¹,

Bravo²,

Ramı́rez³

et al. 1999

J. Clin. Invest.

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“…These changes were associated with the development of poorly differentiated carcinomas and the acquisition of metastatic abilities (Caulín et al, 1995;Frontelo et al, 1998). These and other studies have shown that the expression of K8 and vimentin, linked to downregulation of basal keratins, is associated with malignant progression of squamous cell carcinomas (Caulín et al, 1993a(Caulín et al, , 1993bLarcher et al, 1992;Markey et al, 1991), and several reports have related coexpression of simple epithelial keratins and vimentin to increased cell migration/invasion (Chu et al, 1996;Hendrix et al, 1997;Schaafsma et al, 1993). Thus, PA2.26-induced reorganization of the actin cytoskeleton could lead to up-regulation of keratin K8 and vimentin and repression of basal keratin K14 expression.…”

Section: Discussionmentioning

confidence: 93%

Ectopic Expression of PA2.26 Antigen in Epidermal Keratinocytes Leads to Destabilization of Adherens Junctions and Malignant Progression

Scholl

Gamallo

Quintanilla

2000

Laboratory Investigation

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SUMMARY: PA2.26 antigen is a small mucin-type transmembrane glycoprotein induced in mouse epidermal keratinocytes during carcinogenesis. It is located at plasma membrane projections, such as microvilli and ruffles, where it interacts with the actin cytoskeleton. Previous studies revealed that ectopic expression of PA2.26 in epidermal MCA3D keratinocytes induces cell surface extensions and increased motility. Here, we show that PA2.26-expressing MCA3D (3D2.26) cell transfectants undergo a phenotypic conversion linked to the acquisition of malignant characteristics. The 3D2.26 cells down-regulate basal keratin K14 and up-regulate vimentin and keratin K8 expression. Immunofluorescence analysis in 3D2.26 cell cultures showed loss of cortical actin filaments and destabilization of adherens junctions mediated by E-and P-cadherin, although both cadherin mRNAs were expressed in the transfectants. When the cadherin protein levels were analyzed in Western blots, no P-cadherin protein or smaller polypeptide E-cadherin forms were detected, suggesting that E-and P-cadherin synthesized in 3D2.26 cells was unstable and proteolytically degraded. Transplantation of 3D2.26 cells into athymic nude mice induced tumors, whereas MCA3D cells and control (3DN) transfectants were not tumorigenic after 72 days postinjection. The phenotype of the tumors was undifferentiated, with mixed regions exhibiting a glandular differentiation pattern in which the presence of numerous surface microvilli was observed at the ultrastructural level. Interestingly, PA2.26 antigen was highly expressed in these microvillous cell surfaces. Tumor cells were vimentin-and K8-positive and showed an aberrant pattern of E-cadherin protein expression in which large cytoplasmic aggregates were found close to the nucleus. Infiltration of tumor cells into lymphatic vessels and the presence of frequent regional lymph node metastases were also observed in the tumors. These results indicate that expression of PA2.26 antigen in premalignant keratinocytes induces a fully transformed and metastatic phenotype, and they suggest an involvement of PA2.26 in malignant progression. (Lab Invest 2000, 80:1749 -1759. P A2.26 antigen was identified as a cell-surface protein of about 45 kDa induced in basal-like keratinocytes and dermal fibroblasts during mouse epidermal carcinogenesis and skin remodeling processes. PA2.26 is absent from cultured nontumorigenic keratinocytes, but it is expressed in carcinoma cell lines and cultured active fibroblasts (Gandarillas et al, 1997). The molecular and biochemical characterization of PA2.26 revealed that it is a small mucin-like transmembrane sialoglycoprotein of 172 amino acids, located at microvilli, filopodia, lamellipodia, and ruffles. In normal tissues, PA2.26 is expressed in different type of cells: in the epithelia of choroid plexuses, ependyma, glomeruli, and alveoli, in all mesothelia, and in endothelia of lymphatic vessels, always concentrated at the apical plasma membranes and microvillous projections (Scholl et al, 1999).OTS-8 an...

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“…Expression of normal differentiation markers such as keratin 1 is lost during progression of mouse squamous tumors (24). In contrast, keratin 8 is not expressed in normal squamous epithelia but is a marker for simple epithelia that is reexpressed on malignant conversion of keratinocytes (25,26). Our results show that Cripto-1 blocks normal differentiation marker expression and induces aberrant differentiation marker expression in mouse keratinocytes through its ability to block TGF-h binding to its receptor, phosphorylation of Smad2 and Smad3, and downstream signaling.…”

Section: Discussionmentioning

confidence: 99%

Cripto-1 Alters Keratinocyte Differentiation via Blockade of Transforming Growth Factor-β1 Signaling: Role in Skin Carcinogenesis

Shukla

Liu

et al. 2008

Molecular Cancer Research

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Cripto-1 is an epidermal growth factor-Cripto/FRL1/ Cryptic family member that plays a role in early embryogenesis as a coreceptor for Nodal and is overexpressed in human tumors. Here we report that in the two-stage mouse skin carcinogenesis model, Cripto-1 is highly up-regulated in tumor promotertreated normal skin and in benign papillomas. Treatment of primary mouse keratinocytes with Cripto-1 stimulated proliferation and induced expression of keratin 8 but blocked induction of the normal epidermal differentiation marker keratin 1, changes that are hallmarks of tumor progression in squamous cancer. Chemical or genetic blockade of the transforming growth factor (TGF)-B1 signaling pathway using the ALK5 kinase inhibitor SB431542 and dominant negative TGF-B type II receptor, respectively, had similar effects on keratinocyte differentiation. Our results show that Cripto-1 could block TGF-B1 receptor binding, phosphorylation of Smad2 and Smad3, TGF-B -responsive luciferase reporter activity, and TGF-B1 -mediated senescence of keratinocytes. We suggest that inhibition of TGF-B1 by Cripto-1 may play an important role in altering the differentiation state of keratinocytes and promoting outgrowth of squamous tumors in the mouse epidermis.

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Expression of Simple Epithelial Keratins 8 and 18 in Epidermal Neoplasia

Cited by 97 publications

References 53 publications

Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8

Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8

Ectopic Expression of PA2.26 Antigen in Epidermal Keratinocytes Leads to Destabilization of Adherens Junctions and Malignant Progression

Cripto-1 Alters Keratinocyte Differentiation via Blockade of Transforming Growth Factor-β1 Signaling: Role in Skin Carcinogenesis

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