切换至 "中华医学电子期刊资源库"

中华普通外科学文献(电子版) ›› 2020, Vol. 14 ›› Issue (04) : 248 -252. doi: 10.3877/cma.j.issn.1674-0793.2020.04.003

所属专题: 文献

论著

趋化因子CXCL1通过整合素β1调控胃癌转移的机制研究
魏哲威1, 张常华2, 何裕隆3,()   
  1. 1. 510080 广州,中山大学附属第一医院胃肠外科中心
    2. 518000 深圳,中山大学附属第七医院消化病中心
    3. 510080 广州,中山大学附属第一医院胃肠外科中心;518000 深圳,中山大学附属第七医院消化病中心
  • 收稿日期:2020-03-13 出版日期:2020-08-01
  • 通信作者: 何裕隆
  • 基金资助:
    国家自然科学基金项目(81702325); 广东省自然科学基金项目(2017A030310565); 中山大学青年教师培育项目(20ykpy68)

CXCL1 promoting the metastases of gastric cancer via integrin β1

Zhewei Wei1, Changhua Zhang2, Yulong He3,()   

  1. 1. Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
    2. Department of Digestive Diseases, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518000, China
    3. Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Department of Digestive Diseases, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518000, China
  • Received:2020-03-13 Published:2020-08-01
  • Corresponding author: Yulong He
  • About author:
    Corresponding author: He Yulong, Email:
引用本文:

魏哲威, 张常华, 何裕隆. 趋化因子CXCL1通过整合素β1调控胃癌转移的机制研究[J/OL]. 中华普通外科学文献(电子版), 2020, 14(04): 248-252.

Zhewei Wei, Changhua Zhang, Yulong He. CXCL1 promoting the metastases of gastric cancer via integrin β1[J/OL]. Chinese Archives of General Surgery(Electronic Edition), 2020, 14(04): 248-252.

目的

探讨过表达趋化因子CXCL1促进胃癌细胞迁移及相关分子机制。

方法

应用胃癌细胞株(SGC-7901、BGC-823),重组慢病毒方法构建过表达CXCL1细胞株,siRNA敲低胃癌细胞表达整合素β1(integrin β1)。Western blotting法检测CXCL1、integrin β1、基质金属蛋白酶(MMP)-2、MMP-9、FAK、SRC和ERK的表达,Transwell实验评估胃癌细胞的迁移能力。

结果

过表达CXCL1的SGC-7901和BGC-823细胞中integrin β1表达水平高于对照细胞,siRNA干扰CXCL1表达后,胃癌细胞integrin β1表达水平下降。外源性CXCL1分别增强SGC-7901和BGC-823细胞迁移能力(2.40±0.44)倍(P=0.002)和(2.08±0.30)倍(P=0.001)。此外,CXCL1还增强FAK、SRC和ERK的磷酸化水平。integrin β1-siRNA可以阻断CXCL1所引起的SGC-7901和BGC-823细胞迁移能力增强(P<0.05)及FAK、SRC和ERK的磷酸化水平。CXCL1调控SGC-7901和BGC-823细胞的MMP-2、MMP-9表达,而敲低integrin β1后MMP-2、MMP-9表达随之下调。MMP抑制剂GM6001抑制7901-CXCL1和823-CXCL1细胞的迁移能力(P<0.05)。

结论

CXCL1通过integrin β1激活FAK-SRC-ERK通路和调控MMP-2、MMP-9的表达,最终调控胃癌细胞迁移。

Objective

To investigate the effect of CXCL1 on the migration of gastric cancer (GC) cells and its potential mechanism.

Methods

Lentivirus particles expressing CXCL1 were constructed to establish a stable CXCL1 overexpressing SGC-7901 cell line (7901-CXCL1-GFP) and BGC-823 cell line (823-CXCL1-GFP). siRNA was utilized to block the expression of CXCL1 and integrin β1 in SGC-7901 and BGC-823 cells. Western blotting was performed to analyze the expression of CXCL1, integrin β1, FAK,SRC, ERK, MMP-2 and MMP-9. Transwell assays were adopted to evaluate the migration of gastric cancer cells.

Results

The expression of integrin β1 was higher in 7901-CXCL1-GFP and 823-CXCL1-GFPcells than that in 7901-GFP and 823-GFP cells. Integrin β1 expression was down-regulated by blocking CXCL1 with siRNA. Blocking integrin β1 by siRNA could inhibit CXCL1-induced migration of SGC-7901and BGC-823 cells. CXCL1 increased the expression of p-FAK, p-SRC and p-ERK in GC cells, which could be blocked by integrin β1 knockdown with siRNA. CXCL1 induced the expression of MMP-2 and MMP-9 in GC cells through integrin β1 signaling, meanwhile knockdown of integrin β1 inhibited the MMP-2 and MMP-9 expression. GM6001, one MMPs inhibitor, significantly reduced CXCL1-induced migration of 7901-CXCL1-GFP and 823-CXCL1-GFP cells (P<0.05).

Conclusion

Overexpressed CXCL1 promotes migration of GC cells by activating FAK-SRC-ERK pathway and regulating the expression of MMP-2, MMP-9 through integrin β1 signaling.

图1 CXCL1调控SGC-7901、BGC-823胃癌细胞中整合素β1(integrin β1)表达(Western blotting法) A为细胞转染CXCL1-siRNA后CXCL1蛋白表达情况;B为细胞转染CXCL1基因过表达重组慢病毒颗粒(LV-CXCL1-GFP)和对照慢病毒颗粒(LV-GFP)后CXCL1蛋白表达情况;C为CXCL1-siRNA和LV-CXCL1-GFP转染对胃癌细胞integrin β1表达的影响
图2 重组人源性CXCL1(50 μg/L)通过整合系β1介导促进SGC-7901和BGC-823细胞的迁移 与正常对照组比较,aP<0.01;CXCL1组与CXCL1+siRNA对照组比较,bP<0.05
图3 CXCL1通过整合素β1(integrin β1)促进胃癌细胞p-FAK、p-SRC和p-ERK表达(Western blotting) A为重组人源性CXCL1(50 μg/L)刺激SGC-7901、BGC-823细胞不同时间对FAK、SRC、ERK磷酸化表达的影响;B为转染integrin β1-siRNA后SGC-7901、BGC-823细胞integrin β1蛋白表达下调;C为重组人源性CXCL1和integrin β1-siRNA在SGC-7901、BGC-823细胞FAK、SRC、ERK磷酸化中的作用
图4 CXCL1和整合素β1(integrin β1)对于胃癌细胞MMP-9、MMP-2表达的影响(Western blotting法) A为检测CXCL1过表达及integrin β1-siRNA (25 nmol/L)转染对胃癌细胞SGC-7901、BGC-823中MMP-9蛋白表达的影响;B为检测CXCL1过表达对胃癌细胞SGC-7901、BGC-823中MMP-2蛋白表达的影响;C为检测过表达CXCL1及integrin β1-siRNA (25 nmol/L)转染对胃癌细胞SGC-7901、BGC-823的MMP-2蛋白表达的影响
图5 基质金属蛋白酶抑制剂GM6001抑制CXCL1介导的胃癌细胞迁移 A为GM6001抑制7901-CXCL1-GFP细胞迁移能力,*P<0.05,但对7901-GFP细胞迁移能力无明显抑制作用;B为GM6001抑制823-CXCL1-GFP细胞迁移能力,*P<0.05,但对823-GFP细胞迁移能力无明显抑制作用
[1]
Cecchinato V, Uguccioni M. Insight on the regulation of chemokine activities[J]. J Leukoc Biol, 2018, 104(2): 295-300.
[2]
Wang D, Sun H, Wei J, et al. CXCL1 is critical for premetastatic niche formation and metastasis in colorectal cancer[J]. Cancer Res, 2017, 77(13): 3655-3665.
[3]
Cheng WL, Wang CS, Huang YH, et al. Overexpression of CXCL1 and its receptor CXCR2 promote tumor invasion in gastric cancer[J]. Ann Oncol, 2011, 22(10): 2267-2276.
[4]
Strell C, Niggemann B, Voss MJ, et al. Norepinephrine promotes the β1-integrin-mediated adhesion of MDA-MB-231 cells to vascular endothelium by the induction of a GROα release[J]. Mol Cancer Res, 2012, 10(2): 197-207.
[5]
Bianconi D, Unseld M, Prager GW. Integrins in the spotlight of cancer[J]. Int J Mol Sci, 2016, 17(12): 2037.
[6]
Hamidi H, Ivaska J. Every step of the way: integrins in cancer progression and metastasis[J]. Nat Rev Cancer, 2018, 18(9): 533-548.
[7]
中国抗癌协会胃癌专业委员会. 胃癌腹膜转移防治中国专家共识[J/CD]. 中华普通外科学文献(电子版), 2017, 11(5): 289-297.
[8]
Wang Z, Wang Z, Li G, et al. CXCL1 from tumor-associated lymphatic endothelial cells drives gastric cancer cell into lymphatic system via activating integrin β1/FAK/AKT signaling[J]. Cancer Lett, 2017, 385: 28-38.
[9]
Kawanishi H, Matsui Y, Ito M, et al. Secreted CXCL1 is a potential mediator and marker of the tumor invasion of bladder cancer[J]. Clin Cancer Res, 2008, 14(9): 2579-2587.
[10]
Bolitho C, Hahn MA, Baxter RC, et al. The chemokine CXCL1 induces proliferation in epithelial ovarian cancer cells by transactivation of the epidermal growth factor receptor[J]. Endocr Relat Cancer, 2010, 17(4): 929-940.
[11]
Xu J, Zhang C, He Y, et al. Lymphatic endothelial cell-secreted CXCL1 stimulates lymphangiogenesis and metastasis of gastric cancer[J]. Int J Cancer, 2012, 130(4): 787-797.
[12]
Hammar E, Parnaud G, Bosco D, et al. Extracellular matrix protects pancreatic beta-cells against apoptosis: role of short- and long-term signaling pathways[J]. Diabetes, 2004, 53(8): 2034-2041.
[1] 杨琳, 尹如铁. 外阴白色病变病因研究及治疗现状[J/OL]. 中华妇幼临床医学杂志(电子版), 2024, 20(02): 157-165.
[2] 郑宝英, 黄小兰, 贾楠, 朱春梅. 儿童难治性肺炎支原体肺炎早期预警指标[J/OL]. 中华实验和临床感染病杂志(电子版), 2024, 18(04): 215-221.
[3] 沈华娟, 庄剑波, 刘春. 幽门螺杆菌感染抗体分型与胃黏膜炎性病变程度及黏膜组织学变化间的相关性[J/OL]. 中华实验和临床感染病杂志(电子版), 2024, 18(03): 156-162.
[4] 李刘庆, 陈小翔, 吕成余. 全腹腔镜与腹腔镜辅助远端胃癌根治术治疗进展期胃癌的近中期随访比较[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 23-26.
[5] 黄一博, 李至彦, 林晨, 陶亮, 王萌, 管文贤. 胃癌根治术中淋巴结示踪剂的研究进展[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(05): 586-588.
[6] 丁关棣, 黄云, 曹震, 刘刚. 胃癌根治术后感染性并发症预测:基于真实世界数据的Nomogram模型开发与验证[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(03): 261-266.
[7] 王鹏, 邵欣欣, 胡海涛, 田艳涛, 钟宇新. 改良MOBS 吻合法在全腹腔镜近端胃大部分切除中的应用[J/OL]. 中华腔镜外科杂志(电子版), 2024, 17(05): 267-270.
[8] 胡海涛, 邵欣欣, 姜玉娟, 王鹏, 李维坤, 卢一鸣, 田艳涛. 十二指肠残端处理对全腹腔镜胃癌根治术后并发症的影响[J/OL]. 中华腔镜外科杂志(电子版), 2024, 17(04): 205-209.
[9] 王泽钦, 洪军, 王雅平, 王健, 蒿汉坤. W型肝脏悬吊技术在全腹腔镜下全胃切除术中的应用[J/OL]. 中华腔镜外科杂志(电子版), 2024, 17(04): 218-221.
[10] 刘先勇, 秦东梅, 张若梅, 李俊娇, 孟春芹, 邬明歆, 王玉红, 赵新鲜, 徐瑞联, 洪文文, 马玲, 仇玮, 周宇. Her2/Hes1在肠型胃癌Correa级联反应3个病理阶段中的表达及意义[J/OL]. 中华细胞与干细胞杂志(电子版), 2024, 14(06): 321-327.
[11] 李晶, 潘侠, 周芳, 汪晶, 洪佳. 普鲁卡因通过上调lncRNA DGCR5抑制胃癌细胞增殖、迁移和侵袭[J/OL]. 中华细胞与干细胞杂志(电子版), 2024, 14(03): 151-158.
[12] 甘曦, 廖鑫. 胃癌旁肿瘤沉积与CT影像学特征、血清指标及病理特征的关联性分析[J/OL]. 中华消化病与影像杂志(电子版), 2024, 14(05): 422-425.
[13] 郭彬焰, 褚衍六. 胃癌分期评估模型的研究现状与展望[J/OL]. 中华胃肠内镜电子杂志, 2024, 11(02): 120-122.
[14] 张其德. 内镜下精准肌层剥离术在伴有黏膜下层纤维化/疤痕的早期胃癌治疗的作用初探(视频)[J/OL]. 中华胃肠内镜电子杂志, 2024, 11(02): 144-144.
[15] 胡陈玥, 葛贤秀, 邓雪婷, 姚家楠, 缪林. 图像增强放大内镜诊断胃癌前病变及早期胃癌[J/OL]. 中华胃肠内镜电子杂志, 2024, 11(01): 47-51.
阅读次数
全文


摘要