Table_3_Apolipoprotein E Overexpression Is Associated With Tumor Progression and Poor Survival in Colorectal Cancer.DOCX

Apolipoprotein E (ApoE) plays a key role in tumorigenesis and progression, such as cell proliferation, angiogenesis and metastasis. ApoE overexpression was associated with aggressive biological behaviors and poor prognosis in a variety of tumor according to previous studies. This study aimed to assess the prognostic value and explore the potential relationship with tumor progression in colorectal cancer (CRC). We collected the expression profiling microarray data from the Gene Expression Omnibus (GEO), investigated the ApoE expression pattern between the primary CRC and liver metastasis of CRC, and then explored the gene with prognostic significance based on the TCGA database. ApoE high expression was associated with poor overall survival (OS, p = 0.015) and progression-free survival (PFS, p = 0.004) based on the public databases. Next, ApoE expression was evaluated in two CRC cohorts by immunohistochemistry, of whom 306 cases were stage II and 201 cases were metastatic liver CRC. In the cohort of the liver metastasis, the ApoE expression was increasing in normal mucosa tissue, primary colorectal cancer (PC), and colorectal liver metastases (CLM) in order. Meanwhile, the level of ApoE expression in stage II tumor sample which had no progression evidence in 5 years was lower than that in PC of synchronous liver metastases. The high ApoE expression in PC was an independent risk factor in both stage II (HR = 2.023, [95% CI 1.297–3.154], p = 0.002; HR = 1.883, [95% CI 1.295-2.737], p = 0.001; OS and PFS respectively) and simultaneous liver metastasis (HR = 1.559, [95% CI 1.096–2.216], p = 0.013; HR = 1.541, [95% CI 1.129–2.104], p = 0.006; OS and PFS respectively). However, the overexpression of ApoE could not predict the benefit from the chemotherapy in stage II. The study revealed that the relevance of the ApoE overexpression in CRC progression, conferring a poor prognosis in CRC patients especially for stage II and simultaneous liver metastasis. These finding may improve the prognostic stratification of patients for clinical strategy selection and promote CRC clinic outcomes.

载脂蛋白E（Apolipoprotein E，ApoE）在肿瘤发生与进展过程中发挥关键作用，涉及细胞增殖、血管生成及转移等生物学过程。既往研究表明，ApoE过表达与多种肿瘤的侵袭性生物学行为及不良预后密切相关。本研究旨在评估ApoE在结直肠癌（Colorectal Cancer，CRC）中的预后价值，并探讨其与肿瘤进展的潜在关联。我们从基因表达综合数据库（Gene Expression Omnibus，GEO）中获取表达谱微阵列数据，分析了结直肠癌原发灶与结直肠癌肝转移灶之间的ApoE表达模式，并基于癌症基因组图谱（The Cancer Genome Atlas，TCGA）数据库筛选具有预后意义的基因。基于公共数据库的分析显示，ApoE高表达与较差的总生存期（Overall Survival，OS，p = 0.015）及无进展生存期（Progression-Free Survival，PFS，p = 0.004）显著相关。随后，我们通过免疫组织化学技术检测了两个结直肠癌队列中的ApoE表达水平，其中包含306例II期结直肠癌患者及201例结直肠癌肝转移患者。在肝转移队列中，ApoE的表达水平依次在正常黏膜组织、结直肠癌原发灶（Primary Colorectal Cancer，PC）及结直肠癌肝转移灶（Colorectal Liver Metastases，CLM）中逐渐升高。同时，5年内无进展证据的II期肿瘤样本中ApoE表达水平，低于伴同步肝转移的结直肠癌原发灶样本。在II期结直肠癌及同步肝转移结直肠癌患者中，结直肠癌原发灶的ApoE高表达均为独立危险因素（II期：HR = 2.023，95%置信区间[CI] 1.297–3.154，p = 0.002；HR = 1.883，95%CI 1.295–2.737，p = 0.001，分别对应OS与PFS；同步肝转移组：HR = 1.559，95%CI 1.096–2.216，p = 0.013；HR = 1.541，95%CI 1.129–2.104，p = 0.006，分别对应OS与PFS）。然而，ApoE过表达无法预测II期结直肠癌患者的化疗获益。本研究揭示了ApoE过表达与结直肠癌进展的相关性，提示其可作为结直肠癌患者（尤其是II期及伴同步肝转移患者）不良预后的标志物。上述研究结果可优化结直肠癌患者的预后分层，助力临床治疗策略的选择，并改善结直肠癌的临床诊疗结局。