S4S8-RPA phosphorylation as an indicator of cancer progression in oral squamous cell carcinomas
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Jeff Rector1, Sasha Kapil2, Kelly J Treude2, Phyllis Kumm1, Jason G. Glanzer1, Brendan M. Byrne1, Shengqin Liu1, Lynette M Smith3, Dominick J DiMaio4, Peter Giannini1, Russell B Smith2, Greg G. Oakley1,5
1Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln NE 68583, USA
2Department of Otolaryngology/Head and Neck Surgery, University of Nebraska Medical Center, Omaha NE 68198, USA
3Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha NE 68198, USA
4Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha NE 68198, USA
5Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha NE 68198, USA
Greg G. Oakley, email: [email protected]
Keywords: replication protein A, squamous cell carcinoma, phosphorylation, tumorigenicity, immunohistochemistry
Received: September 18, 2016 Accepted: December 13, 2016 Published: December 16, 2016
Oral cancers are easily accessible compared to many other cancers. Nevertheless, oral cancer is often diagnosed late, resulting in a poor prognosis. Most oral cancers are squamous cell carcinomas that predominantly develop from cell hyperplasias and dysplasias. DNA damage is induced in these tissues directly or indirectly in response to oncogene-induced deregulation of cellular proliferation. Consequently, a DNA Damage response (DDR) and a cell cycle checkpoint is activated. As dysplasia transitions to cancer, proteins involved in DNA damage and checkpoint signaling are mutated or silenced decreasing cell death while increasing genomic instability and allowing continued tumor progression. Hyperphosphorylation of Replication Protein A (RPA), including phosphorylation of Ser4 and Ser8 of RPA2, is a well-known indicator of DNA damage and checkpoint activation. In this study, we utilize S4S8-RPA phosphorylation as a marker for cancer development and progression in oral squamous cell carcinomas (OSCC). S4S8-RPA phosphorylation was observed to be low in normal cells, high in dysplasias, moderate in early grade tumors, and low in late stage tumors, essentially supporting the model of the DDR as an early barrier to tumorigenesis in certain types of cancers. In contrast, overall RPA expression was not correlative to DDR activation or tumor progression. Utilizing S4S8-RPA phosphorylation to indicate competent DDR activation in the future may have clinical significance in OSCC treatment decisions, by predicting the susceptibility of cancer cells to first-line platinum-based therapies for locally advanced, metastatic and recurrent OSCC.
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