Mechanism of Weichang’an inhibiting invasion and metastasis of orthotopic xenografts of colon cancer in nude mice by targeting ARHGAP25

LIN Yi; ZHANG Yue; ZHU Yingjie; GU Ying; TAO Li

doi:10.16305/j.1007-1334.2022.2201065

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Mechanism of Weichang’an inhibiting invasion and metastasis of orthotopic xenografts of colon cancer in nude mice by targeting ARHGAP25

更新时间：2022-11-12

- Mechanism of Weichang’an inhibiting invasion and metastasis of orthotopic xenografts of colon cancer in nude mice by targeting ARHGAP25
- Shanghai Journal of Traditional Chinese Medicine Vol. 56, Issue 11, Pages: 71-77(2022)
- 作者机构：
  
  1.上海中医药大学附属龙华医院肿瘤科（上海 200023）
- 作者简介：
- 基金信息：
- DOI：10.16305/j.1007-1334.2022.2201065
  CLC：
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林怡,张悦,朱莹杰,等.胃肠安通过靶向ARHGAP25抑制裸鼠结肠癌原位移植瘤侵袭转移的机制研究[J].上海中医药杂志,2022,56(11):71-77.

LIN Yi,ZHANG Yue,ZHU Yingjie,et al.Mechanism of Weichang’an inhibiting invasion and metastasis of orthotopic xenografts of colon cancer in nude mice by targeting ARHGAP25[J].Shanghai Journal of Traditional Chinese Medicine,2022,56(11):71-77.
林怡,张悦,朱莹杰,等.胃肠安通过靶向ARHGAP25抑制裸鼠结肠癌原位移植瘤侵袭转移的机制研究[J].上海中医药杂志,2022,56(11):71-77. DOI： 10.16305/j.1007-1334.2022.2201065.

LIN Yi,ZHANG Yue,ZHU Yingjie,et al.Mechanism of Weichang’an inhibiting invasion and metastasis of orthotopic xenografts of colon cancer in nude mice by targeting ARHGAP25[J].Shanghai Journal of Traditional Chinese Medicine,2022,56(11):71-77. DOI： 10.16305/j.1007-1334.2022.2201065.

摘要

目的,2,研究胃肠安对裸鼠结肠癌原位移植瘤Rho鸟苷三磷酸酶激活蛋白25（ARHGAP25）表达的影响，探索胃肠安抑制结肠癌侵袭转移的分子机制。,方法,2,采用人结肠癌HCT-116细胞制作原位移植瘤模型，将造模后的裸鼠随机分为空载体组、ARHGAP25过表达组、空载体+胃肠安低浓度组和空载体+胃肠安高浓度组，每组6只。比较各组原位移植瘤的瘤质量、体积、抑瘤率；免疫组织化学法检测原位移植瘤中ARHGAP25阳性表达；RT-PCR法检测原位移植瘤中,ARHGAP25, mRNA表达，Western blot法检测ARHGAP25、基质金属蛋白酶7（MMP-7）、基质金属蛋白酶9（MMP-9）、E盒结合锌指蛋白1（ZEB1）及β-连环蛋白（β-catenin）的表达。,结果,2,各组裸鼠原位移植成瘤率为100%。ARHGAP25过表达组、空载体+胃肠安低浓度组和空载体+胃肠安高浓度组的抑瘤率分别为88.03%、22.79%和51.48%。ARHGAP25过表达组的原位移植瘤质量较空载体组显著减少（,P,<,0.05）；ARHGAP25过表达组和空载体+胃肠安高浓度组的原位移植瘤体积较空载体组显著减小（,P,<,0.05）。与空载体组相比，ARHGAP25过表达组、空载体+胃肠安低浓度组原位移植瘤中ARHGAP25阳性表达面积显著升高（,P,<,0.05）；ARHGAP25过表达组、空载体+胃肠安低浓度组、空载体+胃肠安高浓度组的原位移植瘤,ARHGAP25, mRNA的表达显著上调（,P,<,0.05）；ARHGAP25过表达组、空载体+胃肠安低浓度组、空载体+胃肠安高浓度组的原位移植瘤ARHGAP25蛋白表达显著上调（,P,<,0.05），MMP-7、MMP-9、ZEB1及β-catenin蛋白表达明显下调（,P,<,0.05）。,结论,2,胃肠安可抑制裸鼠结肠癌原位移植瘤的生长，促进ARHGAP25表达，降低上皮-间充质转化相关分子ZEB1、β-catenin、MMP-7及MMP-9的表达，抑制结肠癌裸鼠原位移植瘤的侵袭转移。

Abstract

Objective,2,To study the effect of Weichang’an on the expression of Rho guanosine triphosphatase activating protein 25 （ARHGAP25） in orthotopic xenografts of colon cancer in nude mice， and to explore the molecular mechanism of Weichang’an inhibiting the invasion and metastasis of colon cancer.,Methods,2,The orthotopic xenograft model was made by human colon cancer HCT-116 cells. The nude mice were randomly divided into empty vector group， ARHGAP25 overexpression group， empty vector + Weichang’an low concentration group and empty vector + Weichang’an high concentration group with 6 mice in each group. The body mass， volume and tumor inhibition rate of orthotopic xenografts were compared. The positive expression of ARHGAP25 was detected by immunohistochemistry， the expression of ,ARHGAP25 ,mRNA was detected by RT-PCR， and the protein expressions of ARHGAP25， matrix metalloproteinase-7 （MMP-7）， matrix metalloproteinase-9 （MMP-9）， E-box binding zinc finger protein 1 （ZEB1） and β-catenin （β-catenin） were detected by Western blot.,Results,2,The rate of tumor formation in nude mice was 100%. The tumor inhibition rates of ARHGAP25 overexpression group， empty vector + Weichang’an low concentration group and empty vector + Weichang’an high concentration group were 88.03%， 22.79% and 51.48%， respectively. The weight of orthotopic xenografts in ARHGAP25 overexpression group was significantly lower than that in empty vector group （,P,<,0.05）； the volume of orthotopic xenografts in ARHGAP25 overexpression group and empty vector + Weichang’an high concentration group was significantly smaller than that in empty vector group （,P,<,0.05）. Compared with those in the empty vector group， the positive expression area of ARHGAP25 was significantly increased in ARHGAP25 overexpression group and empty vector + Weichang’an low concentration group （,P,<,0.05）； the expression of ,ARHGAP25, mRNA was significantly up-regulated in ARHGAP25 overexpression group， empty vector + Weichang’an low concentration group and empty vector + Weichang’an high concentration group （,P,<,0.05）； the expression of ARHGAP25 protein was significantly up-regulated （,P,<,0.05）， while the expression of MMP-7， MMP-9， ZEB1 and β-catenin were significantly down-regulated （,P,<,0.05） in ARHGAP25 overexpression group， empty vector + Weichang’an low concentration group and empty vector + Weichang’an high concentration group.,Conclusion,2,Weichang'an can inhibit the growth of orthotopic xenografts of colon cancer in nude mice， promote the expression of ARHGAP25， reduce the expression of epithelial-mesenchymal transition-related molecules including ZEB1， β-catenin， MMP-7 and MMP-9， restrict the invasion and metastasis of orthotopic colon cancer in nude mice.

关键词

结肠癌胃肠安Rho鸟苷三磷酸酶激活蛋白25上皮-间充质转化肿瘤转移中药研究

Keywords

colon cancerWeichang’anARHGAP25epithelial-mesenchymal transitiontumor metastasistraditional Chinese herbal medicine research

references

BRAY F， FERLAY J， SOERJOMATARAM I， et al. Global cancer statistics 2018： GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］. CA Cancer J Clin， 2018， 68（6）： 394-424.

郑莹，王泽洲. 全球结直肠癌流行数据解读［J］. 中华流行病学杂志，2021， 42（1）： 149-152.

THOMPSON E W， NEWGREEN D F， TARIN D. Carcinoma invasion and metastasis： a role for epithelial-mesenchymal transition？［J］. Cancer Res， 2005， 65（14）： 5991-5995.

BRABLETZ T， HLUBEK F， SPADERNA S， et al. Invasion and metastasis in colorectal cancer： epithelial-mesenchymal transition， mesenchymal-epithelial transition， stem cells and beta-catenin［J］. Cells Tissues Organs， 2005， 179（1-2）： 56-65.

RATH N， OLSON M F. Rho-associated kinases in tumorigenesis： re-considering ROCK inhibition for cancer therapy［J］. EMBO Rep， 2012， 13（10）： 900-908.

ELLENBROEK S I， COLLARD J G. Rho GTPases： functions and association with cancer［J］. Clin Exp Metastasis， 2007， 24（8）： 657-672.

TAO L， ZHU Y J， GU Y， et al. ARHGAP25： A negative regulator of colorectal cancer （CRC） metastasis via the Wnt/β-catenin pathway［J］. Eur J Pharmacol， 2019， 858： 172476.

TAO L， GU Y， ZHENG J， et al. Weichang’an suppressed migration and invasion of HCT116 cells by inhibiting Wnt/β-catenin pathway while upregulating ARHGAP25［J］. Biotechnol Appl Biochem， 2019， 66（5）： 787-793.

黄继汉，黄晓晖，陈志扬，等. 药理试验中动物间和动物与人体间的等效剂量换算［J］. 中国临床药理学与治疗学，2004， 9（9）： 1069-1072.

LEE K K， RAJAGOPALAN D， BHATIA S S， et al. The oncogenic E3 ligase TRIP12 suppresses epithelial-mesenchymal transition （EMT） and mesenchymal traits through ZEB1/2［J］. Cell Death Discov， 2021，7（1）：95.

刘锟荣，韦宜宾，陈国忠. Wnt/β-catenin、TGF-β/Smads及RAS/MARK信号通路与大肠癌关系的研究进展［J］. 广东医学，2014， 35（17）： 2785-2788.

URUSHIBARA F， SHIOZAWA E， MIYACHI H， et al. Expression of matrix metalloproteinase-7 correlates with the invasion of T1 colorectal carcinoma［J］. Oncol Lett， 2018， 15（3）： 3614-3620.

NWOGU N， ORTIZ L E， WHITEHOUSE A， et al. Merkel cell polyomavirus small tumor antigen activates Matrix Metallopeptidase-9 gene expression for cell migration and invasion［J］. J Virol， 2020， 94（19）： e00786-20.

陶丽，朱莹杰，顾缨，等. ARHGAPs分子与结直肠癌侵袭及转移关系的研究进展［J］. 现代肿瘤医学，2018， 26（9）： 1450-1454.

HUANG W K， CHEN Y， SU H， et al. ARHGAP25 inhibits pancreatic adenocarcinoma growth by suppressing glycolysis via AKT/mTOR pathway［J］. Int J Biol Sci， 2021， 17（7）： 1808-1820.

XU K， LIU B， MA Y. The tumor suppressive roles of ARHGAP25 in lung cancer cells［J］. Onco Targets Ther， 2019， 12： 6699-6710.

林怡，陶丽. 结直肠癌转移的中医理论构想［J］. 上海中医药杂志，2020， 54（2）： 6-9.

冯媛媛，周利红，李琦. 健脾法治疗大肠癌的进展及研究现状［J］. 中华中医药杂志，2015， 30（11）： 4013-4015.

顾缨，韩颖盈，郑坚，等. 胃肠安治疗大肠癌临床疗效分析［J］. 辽宁中医药大学学报，2006， 8（5）： 5-6.

陶丽，朱莹杰，顾缨，等. 基于生存分析的胃肠安方辨证治疗对不可切除性结直肠癌肝转移预后影响的双向队列研究［J］. 上海中医药杂志，2017， 51（1）： 42-49.

陶丽，顾缨，吴斌，等. 复方胃肠安对人大肠癌裸鼠原位移植瘤生长和肝转移的影响［J］.上海中医药杂志，2013， 47（4）： 79-84.

TAO L， YANG J K， GU Y， et al. Weichang’an and 5-fluorouracil suppresses colorectal cancer in a mouse model［J］. World J Gastroenterol， 2015， 21（4）： 1125-1139.

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