Department of Biochemistry, Shanxi Medical University, Taiyuan, 030001, Shanxi Province, China.
Department of Pathology, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
Lipids Health Dis. 2022 Feb 16;21(1):22. doi: 10.1186/s12944-022-01629-7.
Colorectal cancer (CRC) is one of the most common cancers worldwide characterized by disparities in age, gender, race and anatomic sites. The mechanism underlying pathogenesis, progression and disparities of CRC remains unclear. This study aims to reveal the association of expression levels of enzymes related to cholesteryl ester (CE) metabolism with pathogenesis, progression and disparities of CRC.
The differences in gene expression levels were analyzed for enzymes in CE synthesis (acyl CoA: cholesterol acyltransferase 1 and 2, ACAT1, and ACAT2), and in CE hydrolysis (neutral cholesterol ester hydrolase, NCEH1 and lysosomal acid lipase, LAL) on TNMplot platform between CRC and normal colorectal tissues (NCT) in a large cohort. The differences in protein expression levels for these enzymes were determined by Immunochemistry (IHC) performed on tissue microarray containing 96 pairs of CRC and benign colorectal tissues (BCT) from different patient populations. The expression level represented as IHC score of each enzyme was compared between CRC and BCT in entire population and populations stratified by race, gender and anatomic sites. Student's t-test, Fisher exact test and ANOVA were used for data analysis. Significant p value was set at P<0.05.
The gene expression level of ACAT1 was significantly lower in CRC than in NCT (P = 2.15e-119). The gene expression level of ACAT2 was not statistically different between CRC and NCT. The gene expression level of LIPA (encoding LAL) was significantly higher in CRC than in NCT (P = 2.01e-14). No data was found for the gene expression level of NCEH1. The IHC score of ACAT1was significantly lower in CRC than in BCT in all studied populations and in sub site of colon, but not in that of rectum. The IHC score of ACAT2 was not statistically different between CRC and BCT. IHC score of NCEH1 was significantly higher in CRC than in BCT only in African American (AA) population. The IHC score of LAL was significantly higher in CRC than in BCT in all studied populations and in all sub sites. In addition, decreased ACAT1 in CRC significantly correlated to progression of CRC: the lower IHC score of ACAT1, the more advanced clinical stage of CRC will be.
This study revealed that altered expression levels in enzymes related to CE metabolism highly correlate to the pathogenesis, clinical progression and disparities of CRC. The results will add revenue in elucidating mechanisms underlying progression of CRC, and shed light on seeking biomarkers and exploring therapeutic targets for CRC in a new direction.
结直肠癌（CRC）是全球最常见的癌症之一，其特征是在年龄、性别、种族和解剖部位方面存在差异。CRC 的发病机制、进展和差异的机制尚不清楚。本研究旨在揭示与胆固醇酯（CE）代谢相关的酶的表达水平与 CRC 的发病机制、进展和差异之间的关联。
在大型队列的 TNMplot 平台上，分析了 CRC 与正常结直肠组织（NCT）之间 CE 合成（酰基辅酶 A：胆固醇酰基转移酶 1 和 2、ACAT1 和 ACAT2）和 CE 水解（中性胆固醇酯水解酶、NCEH1 和溶酶体酸性脂肪酶、LAL）相关酶的基因表达水平差异。通过包含来自不同患者群体的 96 对 CRC 和良性结直肠组织（BCT）的组织微阵列进行免疫化学（IHC），确定了这些酶的蛋白表达水平差异。将每个酶的表达水平表示为整个人群和按种族、性别和解剖部位分层的人群中 CRC 和 BCT 之间的 IHC 评分进行比较。使用 Student's t-test、Fisher exact test 和 ANOVA 进行数据分析。显著的 p 值设置为 P<0.05。
ACAT1 的基因表达水平在 CRC 中明显低于 NCT（P = 2.15e-119）。ACAT2 的基因表达水平在 CRC 和 NCT 之间没有统计学差异。LIPA（编码 LAL）的基因表达水平在 CRC 中明显高于 NCT（P = 2.01e-14）。未发现 NCEH1 的基因表达水平数据。在所有研究人群和结肠亚部位中，CRC 中 ACAT1 的 IHC 评分明显低于 BCT，但在直肠中则不然。CRC 和 BCT 之间的 ACAT2 IHC 评分没有统计学差异。仅在非裔美国人（AA）人群中，CRC 中 NCEH1 的 IHC 评分明显高于 BCT。CRC 中 LAL 的 IHC 评分明显高于 BCT，在所有研究人群和所有亚部位均如此。此外，CRC 中 ACAT1 的表达水平降低与 CRC 的进展高度相关：ACAT1 的 IHC 评分越低，CRC 的临床分期越晚。
本研究表明，与 CE 代谢相关的酶的表达水平改变与 CRC 的发病机制、临床进展和差异高度相关。研究结果将有助于阐明 CRC 进展的机制，并为 CRC 寻求生物标志物和探索新的治疗靶点提供启示。
