Role and mechanism of ACSS2-mediated epithelial-mesenchymal transition in ethanol-promoted migration of colorectal cancer

Yan SUN; Lingqiao WANG; Guowei ZHANG; Fengqiong SUN; Wenyu WANG; Guiyong XU; Aihua ZHANG; Ziyuan ZHOU; Guanghong YANG

doi:10.16016/j.2097-0927.202303141

您当前的位置：

首页 >

文章列表页 >

Role and mechanism of ACSS2-mediated epithelial-mesenchymal transition in ethanol-promoted migration of colorectal cancer

Basic Medicine | 更新时间：2026-01-09

- Role and mechanism of ACSS2-mediated epithelial-mesenchymal transition in ethanol-promoted migration of colorectal cancer
- Journal of Army Medical University Vol. 45, Issue 17, Pages: 1806-1818(2023)
- 作者机构：
  
  1.550025 贵阳，贵州医科大学公共卫生与健康学院
  2.400038 重庆，陆军军医大学(第三军医大学)军事预防医学系环境卫生学教研室
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81273156)
- DOI：10.16016/j.2097-0927.202303141
  CLC： R730.23;R735.35;R595.6
- Received：23 March 2023，
  
  Revised：2023-06-08，
  
  Published：15 September 2023
- 稿件说明：
移动端阅览
Yan SUN, Lingqiao WANG, Guowei ZHANG, et al. Role and mechanism of ACSS2-mediated epithelial-mesenchymal transition in ethanol-promoted migration of colorectal cancer[J]. Journal of Army Medical University, 2023, 45(17): 1806-1818.
DOI：

Yan SUN, Lingqiao WANG, Guowei ZHANG, et al. Role and mechanism of ACSS2-mediated epithelial-mesenchymal transition in ethanol-promoted migration of colorectal cancer[J]. Journal of Army Medical University, 2023, 45(17): 1806-1818. DOI： 10.16016/j.2097-0927.202303141.

摘要

目的

探索

ACSS

acyl-CoA synthetase short chain family member

2)在乙醇促结直肠癌(colorectal cancer，CRC)细胞迁移过程中的作用及其潜在机制。

方法

以在线工具基因表达谱交互式分析(gene expression profiling interactive analysis，GEPIA)和人类蛋白质图谱数据库(the human protein atlas，HPA)分析CRC癌组织和癌旁正常组织中

ACSS

2表达水平；通过ChIP-X富集分析3转录因子数据库(ChIP-X enrichment analysis 3，ChEA3)进行

ACSS

2上游转录因子的富集分析。从癌症基因组图谱(the cancer genome Atlas，TCGA)数据库获得513例CRC患者的

ACSS

2表达水平与相关临床特征参数。以不同浓度乙醇(0、22、44、88 mmol/L)处理HCT116、SW480细胞24、48、72 h，CCK-8实验检测细胞活力；细胞划痕和Transwell实验检测细胞迁移能力；RT-qPCR和Western blot检测相关基因的表达。

结果

① 以22、44、88 mmol/L浓度的乙醇处理48、72 h能显著抑制HCT116和SW480细胞增殖(

＜0.05)。②乙醇处理48 h后，RT-qPCR和Western blot结果显示HCT116、SW480细胞中

ACSS

2的表达明显增加；细胞划痕和Transwell结果显示细胞愈合率和穿孔细胞数均明显增加(

＜0.05)；上皮间质转化(epithelial-mesenchymal transformation，EMT

)相关蛋白E-cadherin表达降低、N-cadherin和Vimentin表达升高(

＜0.05)。③抑制ACSS2表达后，细胞愈合率和穿孔细胞数均较未抑制组降低(

＜0.05)；E-cadherin蛋白表达增加、而N-cadherin和Vimentin蛋白表达降低(

＜0.05)。④HPA数据库分析提示，

ACSS

2在CRC癌组织中的表达明显高于正常组织，其上游调控因子的富集分析提示有8个转录因子可能与ACSS2的表达调控有关，Western blot验证乙醇处理后转录因子CEBPB、SMC1A、CTCF在SW480和HCT116细胞中的表达均显著上调，与ACSS2的表达增加变化一致。⑤513例CRC患者中，

ACSS

2相对高表达组出现外周神经、血管浸润或发生其他远处转移者的比例明显高于相对低表达组(

=6.411，

=0.011)。

结论

乙醇作用后由相关转录因子引起的ACSS2表达增加可能通过诱导EMT促进结直肠癌细胞迁移。

Abstract

Objective

To explore the role and underlying mechanisms of

Acyl-CoA synthetase short chain family member

2 (

ACSS

2) in ethanol-promoted migration of colorectal cancer (CRC) cells.

Methods

The

ACSS

2 expression level in cancer tissues and adjacent normal tissues was analyzed by online tools Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA). The transcription factor enrichment analysis tool ChIP-X Enrichment Analysis 3 (ChEA3) was used to identify

ACSS

2 upstream transcription factors. The

ACSS

2 expression level in cancer tissue and related clinical characteristic parameters of 513 CRC patients were obtained from The Cancer Genome Atlas (TCGA) database. After HCT116 and SW480 cells were treated with ethanol at a dose of 0

44 and 88 mmol/L for 24

48 and 72 h

respectively

cell viability

migration and expression of related molecules at mRNA and protein levels were detected with CCK-8 assay

cell scratch test and transwell assay

and RT-qPCR and Western blotting respectively.

Results

① After treated by ethanol for 48 and 72 h

the 3 doses of 22

44 and 88 mmol/L showed a significant inhibition of proliferation for both HCT116 and SW480 cells (

0.05). ②After 48 h of ethanol treatment

RT-qPCR and Western blotting revealed that the expression levels of

ACSS

2 were increased significantly in HCT116 and SW480 cells

cell scratch test and Transwell assay indicated that the cell healing rate and number of perforated cells were also increased obviously (

0.05)

and epithelial-mesenchymal transformation (EMT) related proteins

E-cadherin was down-regulated

while N-cadherin and Vimentin were up-regulated (all

0.05). ③ Inhibition of

ACSS

2 expression resulted in obviously decreased cell healing rate and number of perforated cells (

0.05)

enhanced expression level of E-cadherin and decrased levels of N-cadherin and Vimentin (all

0.05). ④ HPA database analysis showed that

ACSS

2 has a significantly higher expression level in CRC cancer tissues than in normal tissues

and upstream regulators enrichment analysis suggested 8 transcription factors which probably regulate

ACSS

2 expression. Western blotting showed CEBPB

SMC1A and CTCF had notably increased expression in both SW480 and HCT116 cells after ethanol treatment

which was consistent with the increase trend of

ACSS

2 expression. ⑤ Of the 513 CRC patients

those with higher

ACSS

2 expression had a significantly higher incidence of peripheral nerve or vascular infiltration

and higher rate of existed distant metastases than those with lower expression (

Chi

-square=6.411

=0.011).

Conclusion

Ethanol treatment may probably induce EMT by upregulating

ACSS

2 expression and its upstream transcription factors to promote the migration of CRC cells.

关键词

Keywords

references

Alcohol[EB/OL]. https://www.who.int/news-room/fact-sheets/detail/alcohol. 2022-05-09/2023-06-02.

DEKKER E, TANIS P J, VLEUGELS J L A, et al . Colorectal cancer[J ] . Lancet, 2019, 394(10207): 1467-1480. DOI: 10.1016/s0140-6736(19)32319-0.

BA RDIA A, LOPRINZI C, GROTHEY A, et al . Adjuvant chemotherapy for resected stage Ⅱ and Ⅲ colon cancer: comparison of two widely used prognostic calculators[J ] . Semin Oncol, 2010, 37(1): 39-46. DOI: 10.1053/j.seminoncol.2009.12.005.

DALERBA P, SAHOO D, PAIK S, et al . CDX2 as a prognostic biomarker in stage Ⅱ and stage Ⅲ colon cancer[J ] . N Engl J Med, 2016, 374(3): 211-222. DOI: 10.1056/NEJMoa1506597.

SEITZ H K, ONETA C M. Gastrointestinal alcohol dehydrogenase[J]. Nutr Rev, 1998, 56(2): 52-60. DOI: 10.1111/j.1753-4887.1998.tb01692.x.

SEITZ H K, STICKEL F, HOMANN N. Pathogenetic mechanisms of upper aerodigestive tract cancer in alcoholics[J]. Int J Cancer, 2004, 108(4): 483-487. DOI: 10.1002/ijc.11600.

TUYNS A J. Oesophageal cancer in non-smoking drinkers and in non-drinking smokers[J]. Int J Cancer, 1983, 32(4): 443-444. DOI: 10.1002/ijc.2910320408.

BRUGERE J, GUENEL P, LECLERC A, et al . Differential effects of tobacco and alcohol in cancer of the larynx, pharynx, and mouth[J ] . Cancer, 1986, 57(2): 391-395. DOI: 10.1002/1097-0142(19860115)57:2391:aid-cncr2820570235 > 3.0.co;2 -q.

KUNE G A, VITETTA L. Alcohol consumption and the etiology of colorectal cancer: a review of the scientific evidence from 1957 to 1991[J]. Nutr Cancer, 1992, 18(2): 97-111. DOI: 10.1080/01635589209514210.

BOFFETTA P, HASHIBE M. Alcohol and cancer[J]. Lancet Oncol. 2006;7(2): 149-156. DOI: 10.1016/S1470-2045(06)70577-0.

SCHEPPACH W, BINGHAM S, BOUTRON-RUAULT M C, et al . WHO consensus statement on the role of nutrition in colorectal cancer[J ] . Eur J Cancer Prev, 1999, 8(1): 57-62. DOI: 10.1097/00008469-199902000-00008.

STICKEL F, SCHUPPAN D, HAHN E G, et al . Cocarcinogenic effects of alcohol in hepatocarcinogenesis[J ] . Gut, 2002, 51(1): 132-139. DOI: 10.1136/gut.51.1.132.

ZHENG K H, YU J L, CHEN Z T, et al . Ethanol promotes alcohol-related colorectal cancer metastasis via the TGF-β/RUNX3/Snail axis by inducing TGF-β1 upregulation and RUNX3 cytoplasmic mislocalization[J ] . E Bio Medicine, 2019, 50: 224-237. DOI: 10.1016/j.ebiom.2019.11.011.

SEITZ H K, SIMANOWSKI U A, GARZON F T, et al . Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat[J ] . Gastroenterology, 1990, 98(2): 406-413. DOI: 10.1016/0016-5085(90)90832-l.

SALASPURO M. Bacteriocolonic pathway for ethanol oxidation: characteristics and implications[J]. Ann Med, 1996, 28(3): 195-200. DOI: 10.3109/07853899609033120.

LI C J, CHIU Y H, CHANG C, et al . Acetyl coenzyme A synthase 2 acts as a prognostic biomarker associated with immune infiltration in cervical squamous cell carcinoma[J ] . Cancers (Basel), 2021, 13(13): 3125. DOI: 10.3390/cancers13133125.

COMERFORD S A, HUANG Z G, DU X L, et al . Acetate dependence of tumors[J ] . Cell, 2014, 159(7): 1591-1602. DOI: 10.1016/j.cell.2014.11.020.

MASHIMO T, PICHUMANI K, VEMIREDDY V, et al . Acetate is a bioenergetic substrate for human glioblastoma and brain metastases[J ] . Cell, 2014, 159(7): 1603-1614. DOI: 10.1016/j.cell.2014.11.025.

ZHANG J, LIU D, FENG Z, et al . MicroRNA-138 modulates me tastasis and EMT in breast cancer cells by targeting vimentin[J ] . Biomedecine Pharmacother, 2016, 77: 135-141. DOI: 10.1016/j.biopha.2015.12.018.

LABELLE M, BEGUM S, HYNES R O. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis[J]. Cancer Cell, 2011, 20(5): 576-590. DOI: 10.1016/j.ccr.2011.09.009.

夏宜馨, 张国伟, 王灵巧, 等. 乙醇通过促进上皮间质转化增强结直肠癌细胞的侵袭转移能力[J]. 第三军医大学学报, 2020, 42(15): 1501-1510. DOI: 10.16016/j.1000-5404.202004195.

XIA Y X, ZHANG G W, WANG L Q, et al . Ethanol promotes migration and invasion in colorectal cancer cells via epithelial-mesenchymal transition[J ] . J Third Mil Med Univ, 2020, 42(15): 1501-1510. DOI: 10.16016/j.1000-5404.202004195.

于童. ACSS2在结直肠癌中及TEAD4在溃结中的作用研究[D]. 上海: 上海交通大学. 2017.

YU T. Study on the role of ACSS2 in colorectal cancer and TEAD4 in ulcerative colitis[D]. Shanghai: Shanghai Jiao Tong University, 2017.

LIANG Y D, PI H F, LIAO L Z, et al . Cadmium promotes breast cancer cell proliferation, migration and invasion by inhibiting ACSS2/ATG5-mediated autophagy[J ] . Environ Pollut, 2021, 273: 116504. DOI: 10.1016/j.envpol.2021.116504.

ALDINUCCI D, GLOGHINI A, PINTO A, et al . The classical Hodgkin's lymphoma microenvironment and its role in promoting tumour growth and immune escape[J ] . J Pathol, 2010, 221(3): 248-263. DOI: 10.1002/path.2711.

MANTOVANI A, ALLAVENA P, SICA A, et al . Cancer-related inflammation[J ] . Nature, 2008, 454(7203): 436-444. DOI: 10.1038/nature07205.

MEADOWS S A, VEGA F, KASHISHIAN A, et al . PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma[J ] . Blood, 2012, 119(8): 1897-1900. DOI: 10.1182/blood-2011-10-386763.

BEN-BARUCH A. The tumor-promoting flow of cells into, within and out of the tumor site: regulation by the inflammatory axis of TNFα and chemokines[J]. Cancer Microenviron, 2012, 5(2): 151-164. DOI: 10.1007/s12307-011-0094-3.

KOIVISTO T, SALASPURO M. Acetaldehyde alters proliferation, differentiation and adhesion properties of human colon adenocarcinoma cell line Caco-2[J]. Carcinogenesis, 1998, 19(11): 2031-2036. DOI: 10.1093/carcin/19.11.2031.

赵浩东. 酒精上调CCL5表达通过激活AMPK通路诱导自噬促进结直肠癌转移[D]. 合肥: 安徽医科大学. 2018.

ZHAO H D. Alcohol upregulates CCL5 expression, induces autophagy by activating AMPK pathway and promotes colorectal cancer metastasis[D]. Hefei: Anhui Medical University. 2018.

MANDAL P. Molecular signature of nitric oxide on major cancer hallmarks of colorectal carcinoma[J]. Inflammopharmacol, 2018, 26(2): 331-336. DOI: 10.1007/s10787-017-0435-z.

MCVICKER B, TUMA D J, LAZURE K E, et al . Alcohol, carcinoembryonic antigen processing and colorectal liver metastases[J ] . Adv Exp Med Biol, 2015, 815: 295-311. DOI: 10.1007/978-3-319-09614-8_17.

NGUYEN A, KIM A H, KANG M K, et al . Chronic alcohol exposure promotes cancer stemness and glycolysis in oral/oropharyngeal squamous cell carcinoma cell lines by activating NFAT signaling[J ] . Int J Mol Sci, 2022, 23(17): 9779. DOI: 10.3390/ijms23179779.

WANG S Y, XU M, LI F F, et al . Ethanol promotes mammary tumor growth and angiogenesis: the involvement of chemoattractant factor MCP-1[J ] . Breast Cancer Res Treat , 2012, 133(3): 1037-1048. DOI: 10.1007/s10549-011-1902-7.

RIBEIRO A F, DE LACERDA R B, CORREIA D, et al . Possible involvement of ACSS 2 gene in alcoholism[J ] . J Neural Transm (Vienna), 2017, 124(9): 1151-1158. DOI: 10.1007/s00702-017-1737-4..

SUN L, KONG Y L, CAO M Q, et al . Decreased expression of acetyl-CoA synthase 2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma[J ] . Cancer Sci, 2017, 108(7): 1338-1346. DOI: 10.1111/cas.13252.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Ethanol promotes migration and invasion in colorectal cancer cells via epithelial-mesenchymal transition

Effect of diosmetin on proliferation, apoptosis and migration of colorectal cancer cells by regulating STX17-AS1/miR-383-5p axis

Effect of transcription elongation factor A (S Ⅱ) like 7 on proliferation, migration, invasion and apoptosis of colorectal cancer cells

Over-expression of endothelin 3 suppresses migration and invasion in colorectal cancer LoVo cells

Knockdown of IL35 inhibits migration and invasion of hepatocellular carcinoma by up-regulating autophagy-related proteins in HCC cells

Related Author

Yixin XIA

Guowei ZHANG

Lingqiao WANG

Qi LONG

Weiyan CHEN

Yao TAN

Jianying YANG

Menglong XIANG

Related Institution

Guiyang Maternal and Child Health Care Hospital

Department of Military Environment Health, Faculty of Military Preventive Medicine, Army Medical University (Third Military Medical University)

School of Public Health, Guizhou Medical University

Department of Gastroenterology, the First Affiliated Hospital of Chongqing Medical University

Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University

⁰