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E7 oncoprotein from human papillomavirus 16 alters claudins expression and the sealing of epithelial tight junctions.

ABSTRACT: Tight junctions (TJs) are cell?cell adhesion structures frequently altered by oncogenic transformation. In the present study the role of human papillomavirus (HPV) 16 E7 oncoprotein on the sealing of TJs was investigated and also the expression level of claudins in mouse cervix and in epithelial Madin?Darby Canine Kidney (MDCK) cells. It was found that there was reduced expression of claudins ?1 and ?10 in the cervix of 7?month?old transgenic K14E7 mice treated with 17??estradiol (E2), with invasive cancer. In addition, there was also a transient increase in claudin?1 expression in the cervix of 2?month?old K14E7 mice, and claudin?10 accumulated at the border of cells in the upper layer of the cervix in FvB mice treated with E2, and in K14E7 mice treated with or without E2. These changes were accompanied by an augmented paracellular permeability of the cervix in 2? and 7?month?old FvB mice treated with E2, which became more pronounced in K14E7 mice treated with or without E2. In MDCK cells the stable expression of E7 increased the space between adjacent cells and altered the architecture of the monolayers, induced the development of an acute peak of transepithelial electrical resistance accompanied by a reduced expression of claudins ?1, ?2 and ?10, and an increase in claudin?4. Moreover, E7 enhances the ability of MDCK cells to migrate through a 3D matrix and induces cell stiffening and stress fiber formation. These observations revealed that cell transformation induced by HPV16 E7 oncoprotein was accompanied by changes in the pattern of expression of claudins and the degree of sealing of epithelial TJs.

SUBMITTER: Uc PY

PROVIDER: S-EPMC7473757 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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E7 oncoprotein from human papillomavirus 16 alters claudins expression and the sealing of epithelial tight junctions.

Uc Perla Yaceli PY Miranda Jael J Raya-Sandino Arturo A Alarcón Lourdes L Roldán María Luisa ML Ocadiz-Delgado Rodolfo R Cortés-Malagón Enoc Mariano EM Chávez-Munguía Bibiana B Ramírez Georgina G Asomoza René R Shoshani Liora L Gariglio Patricio P González-Mariscal Lorenza L

International journal of oncology 20200729 4

Tight junctions (TJs) are cell‑cell adhesion structures frequently altered by oncogenic transformation. In the present study the role of human papillomavirus (HPV) 16 E7 oncoprotein on the sealing of TJs was investigated and also the expression level of claudins in mouse cervix and in epithelial Madin‑Darby Canine Kidney (MDCK) cells. It was found that there was reduced expression of claudins ‑1 and ‑10 in the cervix of 7‑month‑old transgenic K14E7 mice treated with 17β‑estradiol (E2), with inva ...[more]

PMID: 32945372

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Project description:High-risk human papillomavirus oncoproteins E6 and E7 play a major role in HPV-related cancers. One of the main functions of E7 is the degradation of pRb, while E6 promotes the degradation of p53, inactivating the p14ARF-p53 pathway. pRb and p14ARF can repress ribosomal DNA (rDNA) transcription in part by targeting the Upstream Binding Factor 1 (UBF1), a key factor in the activation of RNA polymerase I machinery. We showed, through ectopic expression and siRNA silencing of p14ARF and/or E7, that E7 stimulates UBF1-mediated rDNA gene transcription, partly because of increased levels of phosphorylated UBF1, preventing the inhibitory function of p14ARF. Unexpectedly, activation of rDNA gene transcription was higher in cells co-expressing p14ARF and E7, compared to cells expressing E7 alone. We did not find a difference in P-UBF1 levels that could explain this data. However, p14ARF expression induced E7 to accumulate into the nucleolus, where rDNA transcription takes place, providing an opportunity for E7 to interact with nucleolar proteins involved in this process. GST-pull down and co-immunoprecipitation assays showed interactions between p14ARF, UBF1 and E7, although p14ARF and E7 are not able to directly interact. Co-expression of a pRb-binding-deficient mutant (E7C24G) and p14ARF resulted in EC24G nucleolar accumulation, but not in a significant higher activation of rDNA transcription, suggesting that the inactivation of pRb is involved in this phenomenon. Thus, p14ARF fails to prevent E7-mediated UBF1 phosphorylation, but could facilitate nucleolar pRb inactivation by targeting E7 to the nucleolus. While others have reported that p19ARF, the mouse homologue of p14ARF, inhibits some functions of E7, we showed that E7 inhibits a p53-independent function of p14ARF. These results point to a mutually functional interaction between p14ARF and E7 that might partly explain why the sustained p14ARF expression observed in most cervical pre-malignant lesions and malignancies may be ineffective.

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E7 oncoprotein from human papillomavirus 16 alters claudins expression and the sealing of epithelial tight junctions.

Publications

E7 oncoprotein from human papillomavirus 16 alters claudins expression and the sealing of epithelial tight junctions.

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