Co-Expression of p16INK4A and Laminin 5 γ2 by Microinvasive and Superficial Squamous Cell Carcinomas in Vivo and by Migrating Wound and Senescent Keratinocytes in Culture

Natarajan, Easwar; Saeb, Marcela; Crum, Christopher P.; Woo, Sook Bin; McKee, Phillip H.; Rheinwald, James G.

doi:10.1016/s0002-9440(10)63677-2

Cited by 105 publications

(142 citation statements)

References 56 publications

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“…45 P16 expression is activated in cells in response to basement membrane degradation/invasion and is detected in normal migrating keratinocytes as well as in chronic wounds. 11,27 Less than half of our SCC samples had occasional p16-positive keratinocytes at the tumor front. Others and we have shown previously that p16 is absent from invasive areas of SCCs 17 and our new results support these findings.…”

Section: Discussionmentioning

confidence: 99%

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Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

et al. 2006

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Keratoacanthomas are rapidly growing hyperproliferative skin tumors that may clinically or histologically be difficult to distinguish from well-differentiated squamous cell cancers (SCCs). UV light, trauma, and immune suppression represent their etiological factors. As matrix metalloproteinases (MMPs) are implicated at all stages of tumorigenesis, we investigated the expression profile of several cancer-related MMPs to find markers that would differentiate keratoacanthomas from SCCs and shed light to the pathobiology of keratoacanthoma. Samples from 31 keratoacanthomas and 15 grade I SCCs were studied using immunohistochemistry for MMP-2, -7, -8, -9, -10, -13, and -19 and p16 and laminin-5c2 chain. In situ hybridization for MMP-7, -10, and -13 was performed in a subset of tumors. Keratinocytes with atypia, presence of neovascularization, and composition of the inflammatory infiltrate were graded from hematoxylin-eosin stainings. MMP-7 was present in the epithelium of 4/31 keratoacanthomas and 9/15 SCCs, MMP-8 in 3/30 keratoacanthomas and 0/15 SCCs, but MMP-13 in 16/31 keratoacanthomas and 10/15 SCCs, and MMP-10 in 28/31 keratoacanthomas and all cancers. MMP-9 was detected in the epithelium in 5/31 keratoacanthomas and 8/15 SCCs, whereas MMP-2 was only present in fibroblasts in both tumors. MMP-19 was upregulated in proliferating epithelium of keratoacanthomas as was p16. Cytoplasmic laminin-5c2 was particularly abundant in keratinocytes at the pushing border of MMP-13-positive keratoacanthomas. We conclude that although some MMPs (MMP-10 and -13) are abundantly expressed in keratoacanthomas, the presence of MMP-7 and -9 in their epithelial pushing border is rare and should raise suspicion of SCC. Further, the loss of MMP-19 and p16 could aid in making the differential diagnosis between well-differentiated SCC and keratoacanthoma. Frequent expression of the transformationspecific MMP-13 in keratoacanthomas suggests that they are not benign tumors but incomplete SCCs.

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Section: Discussionmentioning

confidence: 99%

“…27 In keratoacanthomas, p16 was detected in hyperproliferating areas of the tumors independent of the number of atypic keratinocytes or the degree of inflammation ( Figure 3c) (Table 1). However, some specimens had clearly fewer p16-positive cells than others (Table 1).…”

Section: Tumor Suppressor P16mentioning

confidence: 93%

Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

et al. 2006

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“…29 Laminin g 2 is undetectable in normal basal cells but frequently is present in the cytoplasm of basal cells in oral and epidermal dysplasias. 24,29 In the present study, p-S6 and laminin g 2 were scored as positive when present in any basal cells in the section, regardless of the number or proportion of positive cells.…”

Section: Ap Pinto Et Almentioning

confidence: 96%

“…In order to improve retention of antigens for immunostaining, 24 sections were not 'baked' at 50 1C after cutting as is the customary practice in pathology labs. Instead, they were warmed at 37 1C for 30 min before deparaffinizing in xylene and rehydrating through 100, 95, and 70% ethanol and PBS.…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

“…[21][22][23] More recently it was found that laminin g 2 overexpression begins at the preinvasive dysplastic stage of neoplastic progression in the oral epithelium and interfollicular epidermis. 24,25 Squamous cell carcinomas of the interfollicular epidermis, oral cavity, oropharynx, and lung very frequently have gene mutations and amplifications that hyperactivate their EGFR/ERK signaling pathway. [26][27][28] Our recent study identified EGFR/ERK signal pathway hyperactivation as necessary and sufficient to drive laminin g 2 overexpression in cultured human premalignant epithelial and squamous cell carcinoma cell lines and also found that the HPV16 E6 oncoprotein also induces laminin g 2 overexpression.…”

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confidence: 99%

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Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia

et al. 2013

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As life expectancy lengthens, cases of non-viral-associated vulvar squamous cell carcinoma and its precursor lesion, so-called differentiated vulvar intraepithelial neoplasia (VIN), continue to increase in frequency. Differentiated VIN often is difficult to recognize and failure to detect it before invasion results in morbidity and mortality. Thus, identification of a reliable biomarker for this type of lesion would be of great clinical benefit. Our recent studies have identified activation (ser235/236 phosphorylation) of ribosomal protein S6 (p-S6) in basal epithelial cells as an event that precedes and accompanies laminin c 2 overexpression in most preinvasive oral dysplasias. To test this as a potential biomarker of vulvar dysplasia, we immunostained seven differentiated VINs and nine papillomavirusrelated 'classic' VINs, most of which were associated with carcinoma, for p-S6. All carcinomas, all differentiated VINs, and most classic VINs contained regions of p-S6 staining in the basal layer, whereas basal and parabasal cells of normal vulvar epithelium and hyperplastic and inflamed lesions lacking cellular atypia were p-S6 negative. Laminin c 2 was expressed in a subset of VINs, always occurring within basal p-S6 positive regions, as we had found previously for oral dysplasias. Lichen sclerosus is considered a potential precursor of vulvar carcinoma. Two lichen sclerosus lesions of patients with a concurrent carcinoma and one of six lichen sclerosus lesions without atypia or known concurrent carcinoma were basal p-S6 positive. In summary, there is a distinct difference in p-S6 basal cell layer staining between benign and neoplastic vulvar squamous epithelium, with consistent staining of differentiated VIN and of some lichen sclerosus lesions. These results support further studies to assess the potential of p-S6 as a biomarker to identify vulvar lesions at risk of progressing to invasive cancer.

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Expression of Laminin γ2 Proteolytic Fragments in Murine Skin Following Exposure to Sulfur Mustard

Chang

Wang

Chang

et al. 2020

The Anatomical Record

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Laminin-332 is a basement membrane protein composed of three genetically distinct polypeptide chains that actively promote both skin epidermal cell adhesion and migration. Proteolytic fragments of the laminin γ2 chain stimulate migration and scattering of keratinocytes and cancer cells. Sulfur mustard (SM) is a bifunctional alkylating agent that induces separation of basal keratinocytes from the dermal-epidermal junction and invokes a strong inflammatory response leading to delayed wound repair. In the present studies, the role of laminin γ2 in SM-induced skin injury and wound repair was investigated using the mouse ear vesicant model. We found that laminin γ2 chain mRNA was preferentially upregulated in mouse ear skin exposed to SM. In situ hybridization confirmed overexpression of laminin γ2 transcript. Western blot analysis showed increased protein expression of the full-length proform of laminin γ2 and smaller processed fragments of laminin γ2 in skin exposed to SM. Dual immunofluorescence labeling indicated that laminin γ2 fragments are prevalent in suprabasal keratinocytes behind the leading edge in areas of hyperplasia in injured skin. In addition, co-expression of laminin γ2 and the senescent marker, p16 INK4a was found to overlap with the hyperplastic migratory epithelial sheet. This observation is similar to hypermotile keratinocytes reported in invasive carcinoma cells. Overall, our studies indicate that laminin γ2 is preferentially expressed in skin post SM exposure and that protein expression appears to become progressively more fragmented. The laminin γ2 fragments may play a role in regulating SM-induced skin wound repair. Anat

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Co-Expression of p16INK4A and Laminin 5 γ2 by Microinvasive and Superficial Squamous Cell Carcinomas in Vivo and by Migrating Wound and Senescent Keratinocytes in Culture

Cited by 105 publications

References 56 publications

Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas

Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia

Expression of Laminin γ2 Proteolytic Fragments in Murine Skin Following Exposure to Sulfur Mustard

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