APE1通过免疫抑制性肿瘤微环境介导结肠炎相关结直肠癌的发生发展

陈天一; 李超凡; 包灵波; 陈骞; 胡那娜; 杨宇馨; 张蕾; 王东

doi:10.16016/j.2097-0927.202404020

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APE1通过免疫抑制性肿瘤微环境介导结肠炎相关结直肠癌的发生发展

基础医学 | 更新时间：2026-01-09

- APE1通过免疫抑制性肿瘤微环境介导结肠炎相关结直肠癌的发生发展
- APE1 mediates the occurrence and development of colitis-associated colorectal cancer through immunosuppressive tumor microenvironment
- 陆军军医大学学报 2024年46卷第16期页码：1825-1837
- 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：
  
  [王东，E-mail：dongwang64@hotmail.comWANG Dong, E-mail: dongwang64@hotmail.com
- 基金信息：
  
  国家自然科学基金面上项目(82073170)
- DOI：10.16016/j.2097-0927.202404020
  中图分类号： R345;R730.23;R735.35
- 收稿：2024-04-09，
  
  修回：2024-05-28，
  
  纸质出版：2024-08-30
- 稿件说明：
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陈天一, 李超凡, 包灵波, 等. APE1通过免疫抑制性肿瘤微环境介导结肠炎相关结直肠癌的发生发展[J]. 陆军军医大学学报, 2024,46(16):1825-1837.

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.
陈天一, 李超凡, 包灵波, 等. APE1通过免疫抑制性肿瘤微环境介导结肠炎相关结直肠癌的发生发展[J]. 陆军军医大学学报, 2024,46(16):1825-1837. DOI： 10.16016/j.2097-0927.202404020.

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

KELLER D S, WINDSOR A, COHEN R, et al . Colorectal cancer in inflammatory bowel disease: review of the evidence[J ] . Tech Coloproctol, 2019, 23(1): 3-13. DOI: 10.1007/s10151-019-1926-2.

KOBAYASHI T, SIEGMUND B, LE BERRE C, et al . Ulcerative colitis[J ] . Nat Rev Dis Primers, 2020, 6(1): 74. DOI: 10.1038/s41572-020-0205-x.

FANTINI M C, GUADAGNI I. From inflammation to colitis-associated colorectal cancer in inflammatory bowel disease: Pathogenesis and impact of current therapies[J]. Dig Liver Dis, 2021, 53(5): 558-565. DOI: 10.1016/j.dld.2021.01.012.

ANTUAMWINE B B, BOSNJAKOVIC R, HOFMANN-VEGA F, et al . N1 versus N2 and PMN-MDSC: a critical appraisal of current concepts on tumor- associated neutrophils and new directions for human oncology[J ] . Immunol Rev, 2023, 314(1): 250-279. DOI: 10.1111/imr.13176.

WANG C X, ZHENG X C, ZHANG J L, et al . CD300ld on neutrophils is required for tumour-driven immune suppression[J ] . Nature, 2023, 621(7980): 830-839. DOI: 10.1038/s41586-023-06511-9.

GUAN Q D, MORENO S, QING G F, et al . The role and potential therapeutic application of myeloid-derived suppressor cells in TNBS-induced colitis[J ] . J Leukoc Biol, 2013, 94(4): 803-811. DOI: 10.1189/jlb.0113050.

OH S Y, CHO K A, KANG J L, et al . Comparison of experimental mouse models of inflammatory bowel disease[J ] . Int J Mol Med, 2014, 33(2): 333-340. DOI: 10.3892/ijmm.2013.1569.

WHITAKER A M, FREUDENTHAL B D. APE1: a skilled nucleic acid surgeon[J]. DNA Repair, 2018, 71: 93-100. DOI: 10.1016/j.dnarep.2018.08.012.

TELL G, QUADRIFOGLIO F, TIRIBELLI C, et al . The many functions of APE1/Ref-1: not only a DNA repair enzyme[J ] . Antioxid Redox Signal, 2009, 11(3): 601-620. DOI: 10.1089/ars.2008.2194.

SHAH F, LOGSDON D, MESSMANN R A, et al . Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic[J ] . NPJ Precis Oncol, 2017, 1: 19. DOI: 10.1038/s41698-017-0023-0.

HASHIMOTO S, IMAOKA S. Protein-disulfide isomerase regulates the thyroid hormone receptor-mediated gene expression via redox factor-1 through thiol reduction-oxidation[J ] . J Biol Chem, 2013, 288(3): 1706-1716. DOI: 10.1074/jbc.M112.365239.

ORDWAY J M, EBERHART D, CURRAN T. Cysteine 64 of Ref-1 is not essential for redox regulation of AP-1 DNA binding[J]. Mol Cell Biol, 2003, 23(12): 4257-4266. DOI: 10.1128/MCB.23.12.4257-4266.2003.

CODRICH M, COMELLI M, MALFATTI M C, et al . Inhibition of APE1-endonuclease activity affects cell metabolism in colon cancer cells via a p53-dependent pathway[J ] . DNA Repair, 2019, 82: 102675. DOI: 10.1016/j.dnarep.2019.102675..

HONG J Y, OH H H, PARK S Y, et al . Expression of apurinic/apyrimidinic endonuclease 1 in colorectal cancer and its relation to tumor progression and prognosis[J ] . In Vivo, 2023, 37(5): 2070-2077. DOI: 10.21873/invivo.13304.

TAN G, HUANG C Y, CHEN J Y, et al . HMGB1 released from GSDME-mediated pyroptotic epithelial cells participates in the tumorigenesis of colitis-associated colorectal cancer through the ERK1/2 pathway[J ] . J Hematol Oncol, 2020, 13(1): 149. DOI: 10.1186/s13045-020-00985-0.

XU H, LI J, CHEN H, et al . NHE8 deficiency promotes colitis-associated cancer in mice via expansion of Lgr5-expressing cells[J ] . Cell Mol Gastroenterol Hepatol, 2019, 7(1): 19-31. DOI: 10.1016/j.jcmgh.2018.08.005..

SWAFFORD D, SHANMUGAM A, RANGANATHAN P, et al . The wnt-β-catenin-IL-10 signaling axis in intestinal APCs protects mice from colitis-associated colon cancer in response to gut microbiota[J ] . J Immunol, 2020, 205(8): 2265-2275. DOI: 10.4049/jimmunol.1901376.

ZHAO Q, BI Y, ZHONG J, et al . Pristimerin suppresses colorectal cancer through inhibiting inflammatory responses and Wnt/β-catenin signaling[J ] . Toxicol Appl Pharmacol, 2020, 386: 114813. DOI: 10.1016/j.taap.2019.114813.

ZHANG C, ZHANG J T, ZHANG Y L, et al . Identifying neutrophil-associated subtypes in ulc erative colitis and confirming neutrophils promote colitis-associated colorectal cancer[J ] . Front Immunol, 2023, 14: 1095098. DOI: 10.3389/fimmu.2023.1095098.

YIN Y, WAN J, YU J M, et al . Molecular pathogenesis of colitis-associated colorectal cancer: immunity, genetics, and intestinal microecology[J ] . Inflamm Bowel Dis, 2023, 29(10): 1648-1657. DOI: 10.1093/ibd/izad081.

NAGAO-KITAMOTO H, KITAMOTO S, KAMADA N. Inflammatory bowel disease and carcinogenesis[J]. Cancer Metast Rev, 2022, 41(2): 301-316. DOI: 10.1007/s10555-022-10028-4.

LIN Y, CHENG L, LIU Y, et al . Intestinal epithelium-derived BATF3 promotes colitis-associated colon cancer through facilitating CXCL5-mediated neutrophils recruitment[J ] . Mucosal Immunol, 2021, 14(1): 187-198. DOI: 10.1038/s41385-020-0297-3.

MOLLINEDO F. Neutrophil degranulation, plasticity, and cancer metastasis[J]. Trends Immunol, 2019, 40(3): 228-242. DOI: 10.1016/j.it.2019.01.006.

KENNEL K B, GRETEN F R. Immune cell - produced ROS and their impact on tumor growth and metastasis[J]. Redox Biol, 2021, 42: 101891. DOI: 10.1016/j.redox.2021.101891.

ZHONG J H, LI Q J, LUO H Q, et al . Neutrophil-derived reactive oxygen species promote tumor colonization[J ] . Commun Biol, 2021, 4(1): 865. DOI: 10.1038/s42003-021-02376-8.

KONG X H, ZHANG Y, XIANG L W, et al . Fusobacterium nucleatum -triggered neutrophil extracellular traps facilitate colorectal carcinoma progression[J ] . J Exp Clin Cancer Res, 2023, 42(1): 236. DOI: 10.1186/s13046-023-02817-8..

VEGLIA F, SANSEVIERO E, GABRILOVICH D I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity[J]. Nat Rev Immunol, 2021, 21(8): 485-498. DOI: 10.1038/s41577-020-00490-y.

ZHAO H K, WU L, YAN G F, et al . Inflammation and tumor progression: signaling pathways and targeted intervention[J ] . Signal Transduct Target Ther, 2021, 6(1): 263. DOI: 10.1038/s41392-021-00658-5.

WANG Y G, DING Y X, DENG Y J, et al . Role of myeloid-derived suppressor cells in the promotion and immunotherapy of colitis-associated cancer[J ] . J Immunother Cancer, 2020, 8(2): e000609. DOI: 10.1136/jitc-2020-000609.

MA N, LIU Q L, HOU L, et al . MDSCs are involved in the protumorigenic potentials of GM-CSF in colitis-associated cancer[J ] . Int J Immunopathol Pharmacol, 2017, 30(2): 152-162. DOI: 10.1177/0394632017711055.

POH T W, MADSEN C S, GORMAN J E, et al . Downregulation of hematopoietic MUC1 during experimental colitis increases tumor-promoting myeloid-derived suppressor cells[J ] . Clin Cancer Res, 2013, 19(18): 5039-5052. DOI: 10.1158/1078-0432.CCR-13-0278.

VAN DER LEUN A M, THOMMEN D S, SCHUMACHER T N. CD8 + T cell states in human cancer: insights from single-cell analysis[J ] . Nat Rev Cancer, 2020, 20(4): 218-232. DOI: 10.1038/s41568-019-0235-4.

KRUSE B, BUZZAI A C, SHRIDHAR N, et al . CD4 + T cell-induced inflammatory cell death controls immune-evasive tumours[J ] . Nature, 2023, 618(7967): 1033-1040. DOI: 10.1038/s41586-023-06199-x..

THOMMEN D S, SCHUMACHER T N. T cell dysfunction in cancer[J]. Cancer Cell, 2018, 33(4): 547-562. DOI: 10.1016/j.ccell.2018.03.012.

SIQUEIRA P B, DE SOUSA RODRIGUES M M, DE AMORIM Í S S, et al . The APE1/REF-1 and the hallmarks of cancer[J ] . Mol Biol Rep, 2024, 51(1): 47. DOI: 10.1007/s11033-023-08946-9.

WANG Y, ZHANG Y F, LIU Y, et al . Gut-liver axis: liver sinusoidal endothelial cells function as the hepatic barrier in colitis-induced liver injury[J ] . Front Cell Dev Biol, 2021, 9: 702890. DOI: 10.3389/fcell.2021.702890.

KORBECKI J, BARCZAK K, GUTOWSKA I, et al . CXCL1 : gene, promoter, regulation of expression, mRNA stability, regulation of activity in the intercellular space[J ] . Int J Mol Sci, 2022, 23(2): 792. DOI: 10.3390/ijms23020792..

ZHUO C H, WU X Y, LI J, et al . Chemokine (C-X-C motif) ligand 1 is associated with tumor progression and poor prognosis in patients with colorectal cancer[J ] . Biosci Rep, 2018, 38(4): BSR20180580. DOI: 10.1042/BSR20180580.

LIU Z Y, ZHENG M, LI Y M, et al . RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression[J ] . Theranostics, 2019, 9(12): 3659-3673. DOI: 10.7150/thno.32126.

HOFSETH L J, KHAN M A, AMBROSE M, et al . The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation[J ] . J Clin Invest, 2003, 112(12): 1887-1894. DOI: 10.1172/JCI19757.

SAHAKIAN L, ROBINSON A M, SAHAKIAN L, et al . APE1/ref-1 as a therapeutic target for inflammatory bowel disease[J ] . Biomolecules, 2023, 13(11): 1569. DOI: 10.3390/biom13111569.

CANLI O, NICOLAS A M, GUPTA J, et al . Myeloid cell-derived reactive oxygen species induce epithelial mutagenesis[J ] . Cancer Cell, 2017, 32(6): 869-883. e5. DOI: 10.1016/j.ccell.2017.11.004.

BUI T M, BUTIN-ISRAELI V, WIESOLEK H L, et al . Neutrophils alter DNA repair landscape to impact survival and shape distinct therapeutic phenotypes of colorectal cancer[J ] . Gastroenterology, 2021, 161(1): 225-238. e15. DOI: 10.1053/j.gastro.2021.03.027.

HE L Y, KANG Q M, CHAN K I, et al . The immunomodulatory role of matrix metalloproteinases in colitis-associated cancer[J ] . Front Immunol, 2022, 13: 1093990. DOI: 10.3389/fimmu.2022.1093990.

SHORT S P, PILAT J M, BARRETT C W, et al . Colonic epithelial-derived selenoprotein P is the source for antioxidant-mediated protection in colitis-associated cancer[J ] . Gastroenterology, 2021, 160(5): 1694-1708. e3. DOI: 10.1053/j.gastro.2020.12.059.

HSIAO S W, YEN H H, CHEN Y Y. Chemoprevention of colitis-associated dysplasia or cancer in inflammatory bowel disease[J]. Gut Liver, 2022, 16(6): 840-848. DOI: 10.5009/gnl210479.

HORIO Y, UCHINO M, IGETA M, et al . Risk factors for the postoperative recurrence of ulcerative colitis-associated colorectal cancer[J ] . Int J Colorectal Dis, 2023, 38(1): 113. DOI: 10.1007/s00384-023-04410-z.

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