Aldolase B impairs DNA mismatch repair and induces apoptosis in colon adenocarcinoma
Aldolase B impairs DNA mismatch repair and induces apoptosis in colon adenocarcinoma
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醛缩酶 B 损害 DNA 错配修复并诱导结肠腺癌细胞凋亡
DOI：
10.1016/j.prp.2019.152597
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发表时间：
2019-01-01
影响因子：
2.8
通讯作者：
Ye, Feng
中科院分区：
文献类型：
--
作者：
Lian, Jiabian;Xia, Lu;Ye, Feng
有证据表明，DNA修复能力表现为完整的功能碱基切除修复和错配修复（MMR）途径与多种癌症类型的预后有关。醛缩酶B（ALDO B）因其在代谢和糖酵解中的作用而众所周知。ALDOB在结肠腺癌中的表达及其与结肠腺癌预后的关系仍存在争议;此外，ALDOB在DNA MMR中的潜在作用尚未见报道。在这项研究中，我们确定了一个集群的DNA修复相关的蛋白质与ALDOB相互作用的结肠腺癌细胞系HCT 116。来自癌症基因组图谱（TCGA-COAD数据，n = 551）的结肠腺癌数据的表达分析表明，ALDOB mRNA表达在具有微卫星不稳定性（MSI）的标本中显著高于具有微卫星稳定性（MSS）的标本。在预后方面，ALDOB mRNA高表达的结肠腺癌患者的总生存期（OS）较长。在福尔马林固定石蜡包埋（FFPE）患者标本中，ALDOB蛋白的高表达与MMR缺陷（d-MMR）显著相关。ALDOB在结肠腺癌细胞系中的表达显著升高。进一步的证据表明，ALDOB过表达诱导MMR蛋白的功能丧失，而不是影响增殖，进而通过破坏EZH 2-Rad 51表达引起不可逆的DNA损伤，然后通过ERK失活引起凋亡。总之，我们的研究表明，ALDOB高表达损害DNA MMR和诱导细胞凋亡在结肠腺癌。ALDOB可能是一个新的与d-MMR相关的生物标志物，也是结肠腺癌的一个独立预后因素。
Evidence suggests that DNA repair capacity manifested by intact functional base excision repair and mismatch repair (MMR) pathways is related to the prognosis of multiple cancer types. Aldolase B (ALDOB) is well known for its role in metabolism and glycolysis. The expression of ALDOB in colon adenocarcinoma and the relationship between its expression and colon adenocarcinoma prognosis remain controversial; in addition, the potential role of ALDOB in DNA MMR has not yet been reported. In this study, we identified a cluster of DNA repair-related proteins that interact with ALDOB in the colon adenocarcinoma cell line HCT116. Expression analysis of colon adenocarcinoma data from the Cancer Genome Atlas (TCGA-COAD data, n = 551) indicated that ALDOB mRNA expression was significantly higher in specimens with microsatellite instability (MSI) than in specimens with microsatellite stability (MSS). Regarding prognosis, colon adenocarcinoma patients with high ALDOB mRNA expression had longer overall survival (OS). Higher expression of ALDOB protein was significantly correlated with MMR deficiency (d-MMR) in formalin-fixed paraffin-embedded (FFPE) patient specimens. The expression of ALDOB was significantly elevated in colon adenocarcinoma cell lines. Further evidence indicated that rather than affecting proliferation, ALDOB overexpression induced the functional loss of MMR proteins and in turn caused irreversible DNA damage via disrupting EZH2-Rad51 expression and then caused apoptosis by ERK in-activation. Overall, our study demonstrates that high ALDOB expression impairs DNA MMR and induces apoptosis in colon adenocarcinoma. ALDOB may be a new biomarker associated with d-MMR and an independent prognostic factor for colon adenocarcinoma.