PAGE4 promotes prostate cancer cells survive under oxidative stress through modulating MAPK/JNK/ERK pathway
PAGE4 promotes prostate cancer cells survive under oxidative stress through modulating MAPK/JNK/ERK pathway
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PAGE4通过调节MAPK/JNK/ERK通路促进前列腺癌细胞在氧化应激下存活
DOI：
10.1186/s13046-019-1032-3
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发表时间：
2019-01-18
影响因子：
11.3
通讯作者：
Zeng, Yu
中科院分区：
文献类型：
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作者：
Lv, Chengcheng;Fu, Shui;Zeng, Yu
背景前列腺癌（PCa）是全世界男性最常见的癌症之一。氧化应激已被认为是与 PCa 进展病理相关的驱动信号之一。然而，氧化应激与前列腺癌进展的关系仍不清楚。方法采用Western blot、q-RT-PCR和生物信息学分析检测PAGE4的表达。进行彗星试验和膜联蛋白 V/PI 双染色试验来研究氧化应激下的 DNA 损伤和细胞死亡。建立小鼠PCa细胞异种移植模型，验证PAGE4在体内的作用。进行转录组分析以研究氧化应激下 PAGE4 功能的潜在机制。进行蛋白质印迹测定以确定MAPK途径的状态。采用免疫组织化学方法鉴定肿瘤组织中PAGE4蛋白的表达。结果本研究发现氧化应激条件下PCa细胞中PAGE4表达增加。 PAGE4 过表达通过减少 DNA 损伤来保护 PCa 细胞免受氧化应激诱导的细胞死亡。 PAGE4过表达促进PCa细胞体内生长。从机制上讲，PAGE4通过调节MAPK通路促进前列腺癌细胞的存活，具体表现为降低MAP2K4、JNK和c-JUN的磷酸化，但增加ERK1/2的磷酸化。结论我们的研究结果表明，PAGE4通过调节MAPK信号通路在氧化应激下保护PCa细胞免受DNA损伤和凋亡。 PAGE4 表达可作为临床应用的预后生物标志物。
BackgroundProstate cancer (PCa) is one of the most common cancers in male worldwide. Oxidative stress has been recognized as one of the driving signals pathologically linked to PCa progression. Nevertheless, the association of oxidative stress with PCa progression remains unclear.MethodsWestern blot, q-RT-PCR and bioinformatics analyses were used to examine PAGE4 expression. Comet assay and Annexin V/ PI dual staining assay were performed to investigate DNA damage and cell death under oxidative stress. Mouse xenograft model of PCa cells was established to verify the role of PAGE4 in vivo. Transcriptomic analysis was performed to investigate the underlying mechanism for the function of PAGE4 under oxidative stress. Western blot assay was conducted to determine the status of MAPK pathway. Immunohistochemistry was used to identify protein expression of PAGE4 in tumor tissues.ResultsIn this study, we found that PAGE4 expression was increased in PCa cells under oxidative stress condition. PAGE4 overexpression protected PCa cells from oxidative stress-inducing cell death by reducing DNA damage. PAGE4 overexpression promoted PCa cells growth in vivo. Mechanistically, PAGE4 promoted the survival of prostate cancer cells through regulating MAPK pathway which reflected in decreasing the phosphorylation of MAP2K4, JNK and c-JUN but increasing phosphorylation of ERK1/2.ConclusionOur findings indicate that PAGE4 protects PCa cells from DNA damage and apoptosis under oxidative stress by modulating MAPK signalling pathway. PAGE4 expression may serve as a prognostic biomarker for clinical applications.