Elsevier

Human Pathology

Volume 32, Issue 12, December 2001, Pages 1351-1355
Human Pathology

Original Contributions
Loss of cytokeratin 14 expression is related to human papillomavirus type and lesion grade in squamous intraepithelial lesions of the cervix*,**

https://doi.org/10.1053/hupa.2001.29656Get rights and content

Abstract

In a recent study of low-grade cervical squamous intraepithelial lesions (SILs), we reported that infection with both low- and high-risk human papillomaviruses (HPVs) upregulated cyclin A, B, E, and Ki67 expression in basal and suprabasal cells. In view of the intricate link between cell cycle exit, proliferation, and differentiation, we examined the morphologic distribution of cytokeratins 13 and 14 and involucrin expression in 49 low-grade SILs infected with HPV types 6, 11, 16, 18, 31, 33, 39, 42, 43, 44, 45, 51, 52, 56, 58, and 66; 2 lesions contained both low- and high-risk HPVs. The findings were compared with 30 high-grade SILs infected with HPV types 16, 31, 33, 51, 58, 66, and 67; 3 of these were infected with 2 different HPVs. In low-grade lesions, the differentiation markers were expressed normally, showing that differentiation proceeds despite upregulation of cell cycle–associated proteins. Loss of involucrin (3 of 33) and cytokeratin 13 (8 of 33) expression occurred only in the high-grade lesions and was therefore related to lesion grade. Loss of cytokeratin 14 expression was also significantly more frequent in high-grade than in low-grade lesions (19 of 33 v 12 of 51; P <.01). In addition, cytokeratin 14 expression was significantly less frequent in the intermediate and superficial layers of low-grade SILs infected with high-risk HPVs than in those infected with low-risk HPVs (3 of 27 v 14 of 24; P <.001). These findings are consistent with in vitro data and suggest that abnormalities of both cell cycle control and squamous differentiation are important in HPV-associated neoplastic transformation. HUM PATHOL 32:1351-1355. Copyright © 2001 by W.B. Saunders Company

Section snippets

Choice of specimens

Ten control normal cervical tissues from patients with no history of SIL and 49 low-grade SIL specimens were from a previously reported series that examined cyclin expression.1 Ten additional normal cervical biopsy specimens and 30 high-grade SILs were identified from the routine diagnostic files of the Department of Pathology of Royal Liverpool University Hospital, and diagnoses were confirmed by 2 gynecologic pathologists (C.S.H. and I.W.M.).

Six-micrometer parallel formalin-fixed paraffin

HPV typing

The 209-bp β-globin fragment was amplified, showing adequate DNA quality from all tissues. All normal cervical tissue controls were negative for HPV. Twenty-seven low-grade SILs1 were infected with high-risk HPV types (HPV 16, n = 5; 18, n = 4; 31, n = 1; 33, n = 1; 39, n = 2; 51, n = 2; 52, n = 3; 56, n = 1; 58, n = 5; 66, n = 3), and 24 were infected with low-risk HPV types (HPV 6, n = 12; 11, n = 6; 42, n = 3; 43, n = 2; 44, n = 1). Double infections (included in the above figures) were

Discussion

There were 2 main findings in this study: (1) absence of cytokeratin 14 expression is associated with high-risk HPV infection and occurs more frequently in high-grade SILs; and (2) dedifferentiation, with loss of cytokeratin 13 or involucrin expression, occurs only in high-grade lesions. Overall, disruption of squamous differentiation occurred more often in high-grade than in low-grade lesions and was associated with high-risk HPV infection.

In most of the low-grade SILs, cytokeratin 14

Acknowledgements

The authors thank Dr E.-M. de Villiers (Deutches Krebsforschungszentrum, Heidelberg, Germany), Dr G. Orth (Institut Pasteur, Paris, France), Dr Y. Matsukura (National Institute of Health, Tokyo, Japan), and A. T. Lorincz (DiGene Diagnostics, Gaithersburg, MD) for providing HPV plasmid clones.

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  • Expression of papillomavirus L1 proteins regulated by authentic gene codon usage is favoured in G2/M-like cells in differentiating keratinocytes

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    One may argue that co-expression of the L1 protein encoded by HPV6b Nat L1 gene with cyclin B1 is not an association with a cell cycle phase in KCs, probably due to that the differentiating KCs only express B-type cyclins. Based on published studies, the link between cell cycle exit, proliferation and differentiation in KCs is still intricate (Mannik et al., 2009; Southern et al., 2001). Differentiation of KCs in culture does not prohibit cells from re-entering the cell cycle and de-differentiating (Mannik et al., 2009).

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*

Supported by grants from Wellbeing and the Royal College of Obstetricians and Gynaecologists (H1/96) and the University of Liverpool.

**

Address correspondence and reprint requests to C. Simon Herrington, Department of Pathology, University of Liverpool, Royal Liverpool University Hospital, Daulby St, Liverpool L69 3GA, England.

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