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. 2012 Aug 3:12:9.
doi: 10.1186/1472-6890-12-9.

Cell culture model predicts human disease: Altered expression of junction proteins and matrix metalloproteinases in cervical dysplasia

Niina Kivi  1 , Mikko Rönty, Jussi Tarkkanen, Petri Auvinen, Eeva Auvinen
Affiliations

Cell culture model predicts human disease: Altered expression of junction proteins and matrix metalloproteinases in cervical dysplasia

Niina Kivi et al. BMC Clin Pathol. .

Abstract

Background: Cervical cancer is necessarily caused by human papillomaviruses, which encode three oncogenes manifesting their functions by interfering with a number of cellular proteins and pathways: the E5, E6, and E7 proteins. We have earlier found in our microarray studies that the E5 oncogene crucially affects the expression of cellular genes involved in adhesion and motility of epithelial cells.

Methods: In order to biologically validate our previous experimental findings we performed immunohistochemical staining of a representative set of tissue samples from different grades of high-risk human papillomavirus associated cervical disease as well as normal squamous and columnar cervical epithelium. Three-dimensional collagen raft cultures established from E5-expressing and control epithelial cells were also examined. The expression of p16, matrix metalloproteinase (MMP) -7, MMP-16, cytokeratin (CK) 8/18, laminin, E-cadherin and beta-catenin was studied.

Results: In agreement with our previous microarray studies, we found intense staining for E-cadherin and beta-catenin in adherens junctions even in high-grade cervical lesions. Staining for MMP-16 was increased in severe disease as well. No significant change in staining for MMP-7 and cytokeratin 8/18 along with the grade of cervical squamous epithelial disease was observed.

Conclusions: Here we have confirmed, using tissue material from human papillomavirus associated lesions, some of the cellular gene expression modifications that we earlier reported in an experimental system studying specifically the E5 oncogene of papillomaviruses. These findings were partially surprising in the context of cervical carcinogenesis and emphasize that the complexity of carcinogenesis is not yet fully understood. Microarray approaches provide a wide overwiev of gene expression in experimental settings, which may yield biologically valid biomarkers for disease diagnostics, prognosis, and follow-up.

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Figures

Figure 1
Figure 1
Immunohistochemical staining for cellular proteins p16 (fields 1–7), MMP-7 (8–14), MMP-16 (15–21), cytokeratin 8/18 (CK8/18) (fields 22–28), laminin (29–35), E-cadherin (36–42) and beta-catenin (43–49) in different grades of high-risk HPV associated cervical disease. SE, squamous epithelium; CE, columnar epithelium; AIS, adenocarcinoma in situ. Original magnification 20x.
Figure 2
Figure 2
Example of immunohistochemical staining in collagen raft cultures. Staining for E-cadherin and beta-catenin in raft cultures established from human keratinocytes expressing HPV 16 E5 protein (HaCaT-E5) or control cells (HaCaT-pMSG). In each field the surface of the epithelial equivalent is facing upwards. Original magnification 20x.
See this image and copyright information in PMC

References

    1. zur Hausen H. Papillomaviruses in the causation of human cancers – a brief historical account. Virology. 2009;384:260–265. doi: 10.1016/j.virol.2008.11.046. - DOI - PubMed
    1. Klingelhutz AJ, Roman A. Cellular transformation by human papillomaviruses: lessons learned by comparing high- and low-risk viruses. Virology. 2012;424:77–98. doi: 10.1016/j.virol.2011.12.018. - DOI - PMC - PubMed
    1. Crusius K, Auvinen E, Alonso A. Enhancement of EGF- and PMA-mediated MAP kinase activation in cells expressing the human papillomavirus type 16 E5 protein. Oncogene. 1997;15:1437–1444. doi: 10.1038/sj.onc.1201312. - DOI - PubMed
    1. Crusius K, Auvinen E, Steuer B, Gaissert H, Alonso A. The human papillomavirus type 16 E5-protein modulates ligand-dependent activation of the EGF receptor family in the human epithelial cell line HaCaT. Exp Cell Res. 1998;241:76–83. doi: 10.1006/excr.1998.4024. - DOI - PubMed
    1. Conrad Stöppler M, Straight SW, Tsao G, Schlegel R, McCance DJ. The E5 gene of HPV-16 enhances keratinocyte immortalization by full-length DNA. Virology. 1996;223:251–254. doi: 10.1006/viro.1996.0475. - DOI - PubMed