Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, 215001, PR China.
Department of Radiation Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai, China.
Cancer Lett. 2018 Mar 28;417:65-74. doi: 10.1016/j.canlet.2017.12.034. Epub 2018 Jan 3.
As a key regulator of DNA translesion synthesis (TLS) pathway, RAD18 is error-prone and contributes to the accumulation of DNA mutations. We have recently shown that RAD18 is overexpressed in human esophageal squamous cell cancer (ESCC) and acts to promote ESCC progression. The current study aims to understand the molecular mechanism by which RAD18 enhances the invasiveness and metastasis of ESCC cells. We found that RAD18 expression is markedly higher in high T stage ESCCs compared to low T stage groups. Kaplan-Meier analysis showed an inverse correlation between RAD18 expression and patient prognosis. The expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), two vital mediators of cell invasion and proliferation, positively correlated with RAD18 expression in ESCC tissues. Ectopic expression of RAD18 enhanced the motility and invasiveness of ESCC cells as evaluated by wound-healing assays and transwell assays. A xenograft nude mouse model showed that RAD18 promoted the colonization of ESCC cells in vivo. Signaling pathway analysis identified the JNK-MMP cascade as a mediator of RAD18-induced enhancement of ESCC progression. These data demonstrate the underlying mechanism by which RAD18 promotes ESCC progression, suggesting that RAD18 is a promising novel prognostic biomarker and therapeutic target against ESCC.
作为 DNA 跨损伤合成（TLS）途径的关键调节因子，RAD18 易出错，并有助于 DNA 突变的积累。我们最近表明，RAD18 在人食管鳞状细胞癌（ESCC）中过表达，并促进 ESCC 的进展。本研究旨在了解 RAD18 增强 ESCC 细胞侵袭和转移的分子机制。我们发现，RAD18 在高 T 期 ESCC 中表达明显高于低 T 期。Kaplan-Meier 分析显示 RAD18 表达与患者预后呈负相关。基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）的表达，细胞侵袭和增殖的两个重要介质，与 ESCC 组织中 RAD18 的表达呈正相关。RAD18 的异位表达通过划痕愈合实验和 Transwell 实验评估增强了 ESCC 细胞的迁移和侵袭能力。异种移植裸鼠模型表明 RAD18 促进了 ESCC 细胞在体内的定植。信号通路分析确定 JNK-MMP 级联反应是 RAD18 诱导的 ESCC 进展增强的介质。这些数据表明了 RAD18 促进 ESCC 进展的潜在机制，表明 RAD18 是一种有前途的新型 ESCC 预后生物标志物和治疗靶标。
