Apolipoprotein E Overexpression Is Associated With Tumor Progression and Poor Survival in Colorectal Cancer

Abstract

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.

Keywords: Apolipoprotein E (ApoE); biomarkers; chemotherapy; colorectal cancer; prognosis; simultaneous liver metastasis; stage II.

FIGURE 1

Representative immunohistochemistry staining pictures of ApoE expression in CRC tissues Tissue high expression (4X for A, 10X for C) and low expression (4X for B, 10X for D) for the ApoE protein are shown. Each of punched samples is 1.0 mm in the tissue microarrays.

FIGURE 2

ApoE expression pattern in the normal intestinal mucosa, primary tumor and colorectal liver metastasis based on 3 datasets (A, GSE41258, B, GSE62322, C, GSE68468) from GEO and their pooling set (D). N, normal intestinal mucosa; PC, primary colorectal cancer; CLM, colorectal liver metastasis; ^∗∗Represents p-value < 0.01.

FIGURE 3

Expression of the ApoE protein in CRC and Kaplan–Meier Curves based on TCGA database. The tumor was represented by red color and the normal tissue was represented by gray color (A). The ApoE expression box plots were generated based on CRC patient pathological major TNM staging (B). The most extreme value from bottom to top in the box plot represents minimum value, the lower quartile, the median, the upper quartile and the maximum value. The method for differential gene expression analysis is one-way ANOVA, using the pathological stage as a variable for calculating differential expression. The ApoE high expression group was associated with decreased overall survival (C) and disease-free survival (D) in CRC according to the data from TCGA, which were calculated using a log-rank test. CRC, Colorectal cancer; TPM, transcript per million; ^#Represents p-value < 0.05.

FIGURE 4

Prognostic power of ApoE in stage II CRC cohort and liver metastatic CRC cohort. Kaplan–Meier analyses of overall survival and progression free survival in patients with CRC based on the expression of ApoE. OS and PFS according to ApoE expression in stage II CRC (A,B) and liver metastatic CRC (C,D). The relationship between ApoE expression and PFS benefit from adjuvant chemotherapy in patients with stage II CRC. Treatment with 5-FU based chemotherapy was not associated with a higher rate of PFS both in the ApoE high group (E) and the ApoE low group (F).