Abstract
Disruption of gap junctional intercellular communication (GJIC) and/or connexins (gap junction proteins) is frequently reported in malignant cell lines and tumours. Certain human papillomaviruses (HPV) associated with the development of cancers, especially of the cervix, have previously been reported to downregulate GJIC in vitro. There is also evidence for reduced gap junctions in cervical dysplasia. However, many squamous hyperproliferative conditions, including HPV-induced warts, often show extensive upregulation of certain connexins. The association between HPV and GJIC, and the mechanism and consequence of deregulated GJIC in cervical tumour progression, remains unclear. Therefore, using a variety of nonmalignant and malignant cell lines and an organotypic raft-culture system, we investigated the relationship between HPV, gap junctions and tumour progression. Established cervical tumour cell lines carrying HPV were unable to communicate via gap junctions (when assayed by dye-transfer techniques). This correlated with lack of connexin protein expression, while transfection with connexins 26 or 43 led to functional gap junction membrane plaques. On the other hand, immortal but nonmalignant cell lines that contained episomal or integrated HPV-16, but required feeder-layer and growth-factor support, were consistently well coupled, and expressed multiple connexins at membrane junctions. In vitro selection of feeder-layer and growth-factor-independent variants eventually lead to loss of GJIC, which correlated with loss of membrane and increased cytoplasmic connexin 43 localization. However, this was preceded by loss of differentiation and stromal invasion, as assayed on the organotypic raft-culture model. Using this model, a comparison between noncoupled, well-coupled and connexin-transfected cell lines revealed no firm correlation between GJIC and dysplasia, but GJIC appeared to favour increased stratification. These findings demonstrate that loss of GJIC is frequent, but appears to occur more as a consequence of, rather than being the cause of, epithelial dysplasia, and may be influenced by, but is not directly attributable to, HPV.
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Acknowledgements
We are grateful to Dr Edgar Rivedal for the Cx43 antibody, Dr Paul Lambert for the W12E and W12G cell lines, Dr Margaret Stanley for the original W12 cell line, Dr Scott Cuthill for the SiHa and CaSki cell lines, Dr Ian Morgan for the C33a cell line, Dr Susan Jamieson and Dr Hiroshi Yamasaki for the HeLa and HeLa43 cells, and Dr Dale Laird for the Cx43-GFP plasmid. T Aasen was supported by a University of Glasgow PhD grant, and by Roche Products, UK.
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Aasen, T., Hodgins, M., Edward, M. et al. The relationship between connexins, gap junctions, tissue architecture and tumour invasion, as studied in a novel in vitro model of HPV-16-associated cervical cancer progression. Oncogene 22, 7969–7980 (2003). https://doi.org/10.1038/sj.onc.1206709
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DOI: https://doi.org/10.1038/sj.onc.1206709
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