S4S8-RPA phosphorylation as an indicator of cancer progression in oral squamous cell carcinomas.
S4S8-RPA phosphorylation as an indicator of cancer progression in oral squamous cell carcinomas.
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DOI：
10.18632/oncotarget.14001
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发表时间：
2017-02-07
期刊：
影响因子：
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通讯作者：
Oakley GG
中科院分区：
文献类型：
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作者：
Rector J;Kapil S;Treude KJ;Kumm P;Glanzer JG;Byrne BM;Liu S;Smith LM;DiMaio DJ;Giannini P;Smith RB;Oakley GG
与许多其他癌症相比，口腔癌更容易获得。然而，口腔癌通常诊断较晚，导致预后不良。大多数口腔癌是主要由细胞增生和发育不良发展而来的鳞状细胞癌。在这些组织中直接或间接地响应于癌基因诱导的细胞增殖失调而诱导DNA损伤。因此，DNA损伤反应（DDR）和细胞周期检查点被激活。随着发育异常转变为癌症，参与DNA损伤和检查点信号传导的蛋白质发生突变或沉默，减少细胞死亡，同时增加基因组不稳定性并允许肿瘤继续进展。复制蛋白A（RPA）的过度磷酸化，包括RPA 2的Ser 4和Ser 8的磷酸化，是DNA损伤和检查点激活的众所周知的指标。在这项研究中，我们利用S4 S8-RPA磷酸化作为口腔鳞状细胞癌（OSCC）癌症发展和进展的标志物。观察到S4 S8-RPA磷酸化在正常细胞中低，在发育不良中高，在早期肿瘤中中等，在晚期肿瘤中低，基本上支持DDR作为某些类型癌症中肿瘤发生的早期屏障的模型。相反，RPA的总体表达与DDR激活或肿瘤进展无关。利用S4 S8-RPA磷酸化来指示未来有能力的DDR激活可能在OSCC治疗决策中具有临床意义，通过预测癌细胞对局部晚期，转移性和复发性OSCC的一线铂基疗法的敏感性。
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.