李刚;郑君华;徐斌;凌杰;邱伟;王永兵;

• 1:上海健康医学院附属上海市浦东新区人民医院普外科

摘要(Abstract)：

目的探讨辛伐他汀在结直肠癌(CRC)血管生成调控中的作用及分子机制。方法 Western blot法检测HER2和VEGF蛋白表达。采用Matrigel小管形成、MTT、伤口愈合试验和Transwell检测辛伐他汀对CRC小管形成、增殖、迁移和侵袭能力的影响。另外,采用HTC-116和LoVo细胞构建裸鼠移植瘤模型,模型小鼠分成2组,对照组每日注射0.1 ml磷酸盐缓冲盐水,治疗组小鼠每天注射50 mg/kg辛伐他汀。免疫组化方法检测肿瘤CD31表达情况,计算肿瘤微血管密度(MVD)。观察辛伐他汀对裸鼠肿瘤生长及肿瘤血管形成的影响。结果 VEGF和HER2在CRC细胞中表达上调,而辛伐他汀明显降低其表达。辛伐他汀预处理可减少体外内皮细胞小管形成和体内微血管密度。辛伐他汀明显抑制HRG-β1诱导的血管形成。机制研究显示,辛伐他汀通过抑制VEGF分泌而显著抑制HER2诱导引起的肿瘤血管生成。结论辛伐他汀通过对HER2/VEGF轴的调控抑制肿瘤血管生成,为辛伐他汀抑制过表达HER2型CRC提供了一种新的机制。

关键词(KeyWords)： 辛伐他汀;抗血管生成;HER2;VEGF;结直肠癌

Abstract:

Keywords:

基金项目(Foundation): 上海市浦东新区科技发展基金项目(PKJ2016-Y30);; 上海健康医学院种子基金项目(HMSF-16-21-028)

作者(Author): 李刚;郑君华;徐斌;凌杰;邱伟;王永兵;

Email:

DOI: 10.14053/j.cnki.ppcr.201905005

参考文献(References)：

• [1] Bruno A,Bassani B,D′Urso DG,et al.Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic,decidual NK-like cells from patients with colorectal cancer[J].FASEB J,2018,32(10):5365-5377.
• [2] Van Cutsem E,Oliveira J.Advanced colorectal cancer:ESMO clinical recommendations for diagnosis,treatment and follow-up[J].Ann Oncol,2009,20 (Suppl 4):61-63.
• [3] Zhang YY,Chen B,Ding YQ.Metastasis-associated factors facilitating the progression of colorectal cancer[J].Asian Pac J Cancer Prev,2012,13(6):2437-2444.
• [4] Sun W,Wang X,Li J,et al.MicroRNA-181a promotes angiogenesis in colorectal cancer by targeting SRCIN1 to promote the SRC/VEGF signaling pathway[J].Cell Death Dis,2018,9(4):438.
• [5] Desroches-Castan A,Quélard D,Demeunynck M,et al.A new chemical inhibitor of angiogenesis and tumorigenesis that targets the VEGF signaling pathway upstream of Ras[J].Oncotarget,2015,6(7):5382-5411.
• [6] Minami T,Kijima T,Kohmo S,et al.Overcoming chemoresistance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicity and VEGF-targeted antiangiogenesis[J].Sci Rep,2013,3:2669.
• [7] Hsueh SP,Hsu WB,Wen CC,et al.SV40 T/t-common polypeptide inhibits angiogenesis and growth of HER2-overexpressing human ovarian cancer[J].Cancer Gene Ther,2011,18(12):859-870.
• [8] Manu KA,Shanmugam MK,Li F,et al.Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products[J].J Mol Med (Berl),2014,92(3):267-276.
• [9] Wang JC,Li XX,Sun X,et al.Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF-1α-induced pro-angiogenic factor[J].Cancer Sci,2018,109(5):1627-1637.
• [10] Sumi S,Beauchamp RD,Townsend CM,et al.Inhibition of pancreatic adenocarcinoma cell growth by lovastatin[J].Gastroenterology,1992,103(3):982-989.
• [11] Cheng-Qian Y,Xin-Jing W,Wei-Xinbing,et al.Lovastatin inhibited the growth of gastric cancer cells[J].Hepatogastroenterology,2014,61(129):1-4.
• [12] Glynn SA,O′Sullivan D,Eustace AJ,et al.The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors,simvastatin,lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells[J].BMC Cancer,2008,8:9.
• [13] Chen MC,Tsai YC,Tseng JH,et al.Simvastatin inhibits cell proliferation and migration in human anaplastic thyroid cancer[J].Int J Mol Sci,2017,18(12).
• [14] Zhao Z,Cao X,Pan Y,et al.Simvastatin downregulates HER2 via upregulation of PEA3 to induce cell death in HER2-positive breast cancer cells[J].Oncol Res,2012,20(5-6):187-195.
• [15] Zhu XY,Daghini E,Chade AR,et al.Disparate effects of simvastatin on angiogenesis during hypoxia and inflammation[J].Life Sci,2008,83(23-24):801-809.
• [16] Sitohy B,Nagy JA,Dvorak HF.Anti-VEGF/VEGFR therapy for cancer:reassessing the target[J].Cancer Res,2012,72(8):1909-1914.
• [17] Pan MH,Lin YT,Lin CL,et al.Suppression of heregulin-β1/HER2-modulated invasive and aggressive phenotype of breast carcinoma by pterostilbene via inhibition of matrix metalloproteinase-9,p38 kinase cascade and Akt activation[J].Evid Based Complement Alternat Med,2011,2011:562187.