Abstract
The viral oncoprotein E7 from the “high-risk” Human Papillomavirus 16 (HPV16) strain is able, when expressed in human keratinocytes, to physically interact with the actin severing protein gelsolin (GSN). In a previous work it has been suggested that this protein-protein interaction can hinder GSN severing function, thus leading to actin network remodeling. In the present work we investigated the possible implications of this molecular interaction in cancer cell metastatic potential by analyzing two different human CC cell lines characterized by low or high expression levels of HPV16 DNA (SiHa and CaSki, respectively). In addition, a HPV-null CC cell line (C-33A), transfected in order to express the HPV16 E7 oncoprotein as well as two different deletion mutants, was also analyzed. We found that HPV16 E7 expression level was directly related with cervical cancer migration and invasion capabilities and that these HPV16 E7-related features were associated with Epithelial to Mesenchymal Transition (EMT) processes. These effects appeared as strictly attributable to the physical interaction of HPV16 E7 with GSN, since HPV16 E7 deletion mutants unable to bind to GSN were also unable to modify microfilament assembly dynamics and, therefore, cell movements and invasiveness. Altogether, these data profile the importance of the physical interaction between HPV16 E7 and GSN in the acquisition of the metastatic phenotype by CC cells, underscoring the role of HPV16 intracellular load as a risk factor in cancer.
Highlights
The “high-risk” genotypes of Human Papillo maviruses (HPVs) are the most important etiological factors in squamous cervical carcinoma (CC)
The present work was aimed at assessing whether the presence and the expression level of Human Papillomavirus 16 (HPV16) could be relevant for carcinoma cells behavior and, in particular, the specific role of the E7 oncoprotein in the acquisition of a more malignant, pro-metastatic phenotype
In light of our previous data, we evaluated the cellular amount of total actin as well as its monomeric (G-actin, by DNAse I) and polymeric (F-actin, by phalloidin) forms, and the overall morphology of the above CC cell lines
Summary
The “high-risk” genotypes of Human Papillo maviruses (HPVs) are the most important etiological factors in squamous cervical carcinoma (CC). Most of the HPV-induced tumors are characterized by the persistent expression of viral oncogenes and their protein products These oncoproteins can reprogram www.impactjournals.com/oncotarget fundamental cellular functions, generating a significant, partially explored, imbalance in cellular protein molecular networks and cell signaling pathways. All these changes appear finalized to a successful infection and include the survival of the infected cell, but, in a small percentage of cases, they can favor the selection and rise of transformed cell clones [4,5,6,7]. Having no known enzymatic activity, E7 is able to reprogram fundamental cellular functions via specific protein-protein interactions it establishes with a large number of cellular factors [8,9,10]
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