Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Sweden.
Clin Cancer Res. 2012 Mar 1;18(5):1257-67. doi: 10.1158/1078-0432.CCR-11-2058. Epub 2012 Jan 13.
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, SMG-1 (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.
Expression and promoter methylation status of SMG-1 were investigated in HNSCCs. To identify a functional link between HPV infection and SMG-1, we transfected the HPV-negative cells with an E6/E7 expression construct. SMG-1 short hairpin RNAs were expressed in HPV-negative cells to estimate survival upon IR.
Forced E6/E7 expression in HPV-negative cells resulted in SMG-1 promoter hypermethylation and decreased SMG-1 expression. Due to promoter hypermethylation, HPV-positive HNSCC cells and tumors express SMG-1 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.
Levels of SMG-1 expression negatively correlated with HPV status in cancer cell lines and tumors. Diminished SMG-1 expression may contribute to the enhanced response to therapy exhibited by HPV-positive HNSCCs.
人乳头瘤病毒（HPV）与一部分头颈部鳞状细胞癌（HNSCC）有关。HPV 阳性 HNSCC 的预后优于 HPV 阴性 HNSCC，这可能是因为 HPV 阳性 HNSCC 对电离辐射（IR）更敏感。尽管 HPV 阳性 HNSCC 对 IR 敏感的分子机制尚未解决，但 DNA 损伤反应（DDR）可能是 IR 敏感性的重要决定因素。SMG-1（生殖器形态发生效应的抑制因子）是 DDR 中的一个重要参与者，它是一种潜在的肿瘤抑制因子，因此可能在癌症中失调。目前还没有研究将 SMG-1 表达缺陷与癌症联系起来。我们研究了 ORP-HNSCC 中 DDR 缺陷是否与 SMG-1 失调有关。
研究了 HNSCC 中 SMG-1 的表达和启动子甲基化状态。为了确定 HPV 感染与 SMG-1 之间的功能联系，我们用 E6/E7 表达构建体转染了 HPV 阴性细胞。在 HPV 阴性细胞中表达 SMG-1 短发夹 RNA，以估计它们在接受 IR 后的存活情况。
在 HPV 阴性细胞中强制表达 E6/E7 导致 SMG-1 启动子超甲基化和 SMG-1 表达降低。由于启动子超甲基化，HPV 阳性 HNSCC 细胞和肿瘤的 SMG-1 表达水平低于 HPV 阴性 SCC。在 HPV 阴性 HNSCC 细胞中耗尽 SMG-1 导致辐射敏感性增加，而 SMG-1 过表达则使 HPV 阳性肿瘤细胞免受照射。
SMG-1 表达水平与癌症细胞系和肿瘤中的 HPV 状态呈负相关。SMG-1 表达减少可能导致 HPV 阳性 HNSCC 对治疗的反应增强。
