APE1 mediates the occurrence and development of colitis-associated colorectal cancer through immunosuppressive tumor microenvironment

Tianyi CHEN; Chaofan LI; Lingbo BAO; Qian CHEN; Nana HU; Yuxin YANG; Lei ZHANG; Dong WANG

doi:10.16016/j.2097-0927.202404020

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APE1 mediates the occurrence and development of colitis-associated colorectal cancer through immunosuppressive tumor microenvironment

Basic Medicine | 更新时间：2026-01-09

- APE1 mediates the occurrence and development of colitis-associated colorectal cancer through immunosuppressive tumor microenvironment
- Journal of Army Medical University Vol. 46, Issue 16, Pages: 1825-1837(2024)
- 作者机构：
  
  1.400042 重庆，陆军特色医学中心肿瘤中心
  2.400039 重庆，渝粤病理科学研究中心
  3.401329 重庆，金凤实验室
- 作者简介：
- 基金信息：
  
  the General Program of National Science Foundation of China(82073170)
- DOI：10.16016/j.2097-0927.202404020
  CLC： R345;R730.23;R735.35
- Received：09 April 2024，
  
  Revised：2024-05-28，
  
  Published：30 August 2024
- 稿件说明：
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Tianyi CHEN, Chaofan LI, Lingbo BAO, et al. APE1 mediates the occurrence and development of colitis-associated colorectal cancer through immunosuppressive tumor microenvironment[J]. Journal of Army Medical University, 2024, 46(16): 1825-1837.
DOI：

Tianyi CHEN, Chaofan LI, Lingbo BAO, et al. APE1 mediates the occurrence and development of colitis-associated colorectal cancer through immunosuppressive tumor microenvironment[J]. Journal of Army Medical University, 2024, 46(16): 1825-1837. DOI： 10.16016/j.2097-0927.202404020.

摘要

目的

探讨脱嘌呤/脱嘧啶核酸内切酶1(apurinic/apyrimidinic endonuclease 1

APE1)在慢性肠道炎症向结肠炎相关性结直肠癌(colitis-associated colorectal cancer

CAC)转化过程中的调控机制。

方法

将C64S点突变纯合子(APE1

C64S

)和野生型(APE1

)小鼠分别按随机数字表法分为实验组与对照组

实验组应用氧化偶氮甲烷(azoxymethane

AOM)及葡聚糖硫酸钠盐(dextran sulfate sodium salt

DSS)溶液构建CAC体内模型

采用免疫组化及多重免疫荧光分析各组小鼠结肠组织APE1表达及免疫细胞浸润情况。通过慢病毒转染构建APE1稳定敲低的小鼠结肠癌MC38细胞系

并对APE1

与APE1

C64S

小鼠进行皮下荷瘤实验以确定肿瘤细胞来源的APE1导致免疫抑制性肿瘤微环境

采用免疫组化及多重免疫荧光分析荷瘤标本APE1、趋化因子(C-X-C基序)配体1[chemokine (C-X-C motif) ligand 1

CXCL1

]

表达及免疫细胞浸润情况。对来自陆军特色医学中心的1名28岁女性CAC患者的肿瘤标本采用免疫组化及多重免疫荧光分析肿瘤及邻近炎症组织中APE1、CXCL1的表达及免疫细胞浸润情况。

结果

与对照组及APE1

实验组相比

APE1

C64S

实验组小鼠的疾病活动指数及肿瘤形成数量明显降低

多形核髓源抑制细胞(polymorphonuclear myeloid-derived suppressor cells

PMN-MDSCs)浸润显著减少

CD4

及CD8

T细胞显著增多(

0.05)。APE1

与APE1

C64S

皮下荷瘤小鼠肿瘤生长及各免疫细胞差异无统计学意义; 而使用敲低APE1的肿瘤细胞进行荷瘤实验

发现肿瘤生长明显抑制

PMN-MDSCs浸润减少

同时CD4

及CD8

T细胞显著增多(

0.05)。在CAC患者肿瘤组织中APE1高表达、PMN-MDSCs浸润增加

CD8

T细胞在肿瘤组织中较炎症组织浸润显著减少(

0.05)。

结论

肿瘤细胞中APE1的氧化还原功能可促进PMN-MDSCs肿瘤浸润

同时减少T细胞的数量

从而形成免疫抑制性肿瘤微环境介导CAC的发生发展。

Abstract

Objective

To investigate the regulatory mechanism of apurnic/apyrimidinic endonuclease 1(APE1) in the transformation of chronic intestinal inflammation to colitis-associated colorectal cancer (CAC).

Methods

C64S mutant (APE1

C64S

) mice and APE1 wild type (APE1

) mice were randomly divided into experimental group and control group.

In vivo

CAC model was established by azoxymethane (AOM) and dextran sulfate sodium salt (DSS) solution.Immunohistochemistry (IHC) and multiple IHC (mIHC) assays were used to observe the expression of APE1 and immune cell infiltration in colon tissues of each group.A mouse colon cancer cell line MC38 with stable knockdown of APE1 was constructed by lentivirus transfection

and subcutaneous tumor bearing experiments were performed in APE1

and APE1

C64S

mice to confirm that tumor cell-derived APE1 caused immunosuppressive tumor microenvironment.The expression of APE1 and CXCL1[chemokine (C-X-C motif) ligand 1

]

and the infiltration of immune cells in tumor-bearing specimens were analyzed by IHC and mIHC assays.The tumor specimens of a 28-year-old female patient with CAC from Army Medical Center of PLA were analyzed for the expression of APE1 and CXCL1 and the infiltration of immune cells in the tumor and adjacent inflammatory tissues by IHC and mIHC assays.

Results

Compared with the control group and APE1

erperimental group

APE1

C64S

erperimental group had significantly reduced disease activity index and tumor formation

polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) infiltration

and CD4

and CD8

T cells (

0.05).No significant differences were observed in tumor growth and immune cells between APE1

and APE1

C64S

mice bearing subcutaneous tumors.However

in the tumor-bearing experiment using tumor cells with knockdown of APE1

the tumor growth was significantly lower and the number of infiltrated PMN-MDSCs was reduced

while those of CD4

and CD8

T cells were significan

tly increased (

0.05).Furthermore

high expression of APE1 and increased infiltration of PMN-MDSCs were found in the tumor tissues of the young CAC patient

and CD8

T cells were significantly reduced in the tumor tissues compared with the inflammatory tissues (

0.05).

Conclusion

APE1-redox in tumor cells can promote the infiltration of PMN-MDSCs and reduce the number of T cells

thereby forming an immunosuppressive tumor microenvironment and mediating the occurrence and development of CAC.

关键词

Keywords

references

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