Abstract
<div>Abstract<p><b>Purpose:</b> Human papillomavirus (HPV) is linked with a subset of head and neck squamous cell carcinomas (HNSCC). HPV-positive HNSCCs show a better prognosis than HPV-negative HNSCCs, which may be explained by sensitivity of the HPV-positive HNSCCs to ionizing radiation (IR). Although the molecular mechanism behind sensitivity to IR in HPV-positive HNSCCs is unresolved, DNA damage response (DDR) might be a significant determinant of IR sensitivity. An important player in the DDR, <i>SMG-1</i> (suppressor with morphogenetic effect on genitalia), is a potential tumor suppressor and may therefore be deregulated in cancer. No studies have yet been conducted linking defects in SMG-1 expression with cancer. We investigated whether deregulation of SMG-1 could be responsible for defects in the DDR in oropharyngeal HNSCC.</p><p><b>Experimental Design:</b> Expression and promoter methylation status of <i>SMG-1</i> were investigated in HNSCCs. To identify a functional link between HPV infection and SMG-1, we transfected the HPV-negative cells with an <i>E6/E7</i> expression construct. <i>SMG-1</i> short hairpin RNAs were expressed in HPV-negative cells to estimate survival upon IR.</p><p><b>Results:</b> Forced <i>E6/E7</i> expression in HPV-negative cells resulted in <i>SMG-1</i> promoter hypermethylation and decreased <i>SMG-1</i> expression. Due to promoter hypermethylation, HPV-positive HNSCC cells and tumors express <i>SMG-1</i> at lower levels than HPV-negative SCCs. Depletion of SMG-1 in HPV-negative HNSCC cells resulted in increased radiation sensitivity, whereas SMG-1 overexpression protected HPV-positive tumor cells from irradiation.</p><p><b>Conclusions:</b> Levels of <i>SMG-1</i> expression negatively correlated with HPV status in cancer cell lines and tumors. Diminished <i>SMG-1</i> expression may contribute to the enhanced response to therapy exhibited by HPV-positive HNSCCs. <i>Clin Cancer Res; 18(5); 1257–67. ©2012 AACR</i>.</p></div>
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