目的: 研究辛二酰苯胺异羟肟酸(SAHA)是否可以调节RECK蛋白使MMP-2、MMP-9在动物体内表达发生改变,从而达到抑制乳腺癌细胞生长、增殖和转移,改善预后的作用,提供乳腺癌临床治疗新思路。方法: 乳腺癌细胞MCF-7培养后,被移植到裸鼠皮下,制成动物模型。将裸鼠成瘤模型分为对照组(生理盐水 0.4 mL/kg)和实验组(SAHA 0.42 mg/kg),成瘤模型建立后,ELISA方法检测裸鼠体内IL-6的含量。断颈法处死裸鼠,取肿瘤组织称重并计算脏器指数。取肿瘤组织做HE病理性染色。IHC、WB检测MMP-2、MMP-9、RECK在肿瘤组织中的表达。结果: 与对照组相比,实验组IL-6含量、肿瘤重量及脏器指数降低(P＜0.01)。肿瘤组织HE染色显示,实验组以中重度坏死为主,对照组中以轻中度坏死为主。IHC检测显示,与对照组相比,实验组RECK阳性表达较高,MMP-2、MMP-9阳性表达较低(P＜0.05)。WB检测显示,与对照组相比,实验组RECK表达较高,MMP-2、MMP-9表达较低(P＜0.01)。结论: SAHA可在动物体内通过提高RECK蛋白的表达来降低MMP-2、MMP-9的表达,从而抑制了人乳腺癌MCF-7细胞的侵袭和转移。
Objective: To study whether suberoylanilide hydroxamic acid (SAHA ) can regulate RECK protein to change the expression of MMP-2 and MMP-9 in animals, so as to inhibit the growth, proliferation and metastasis of breast cancer cells, improve the prognosis, and provide new ideas for clinical treatment of breast cancer. Methods: The breast cancer cell MCF-7 was cultured and transplanted subcutaneously into nude mice to make an animal model. The nude mouse tumor model was divided into control group ( normal saline 0.4 mL/kg ) and experimental group ( SAHA 0.42 mg/kg). After the tumor model was established, the content of IL-6 in nude mice was detected by ELISA. The nude mice were sacrificed by neck cutting method, and the tumor tissues were weighed and the organ index was calculated. HE pathological staining was performed on tumor tissues. The expression of MMP-2, MMP-9 and RECK in tumor tissues was detected by IHC and WB. Results: Compared with the control group, the IL-6 content, tumor weight and organ index of the experimental group decreased (P＜0.01). HE staining of tumor tissue showed that the experimental group was mainly moderate to severe necrosis, while the control group was mainly mild to moderate necrosis. IHC test showed that compared with the control group, the positive expression of RECK in the experimental group was higher, and the positive expression of MMP-2 and MMP-9 was lower (P＜0.05). WB test showed that compared with the control group, the expression of RECK in the experimental group was higher, and the expression of MMP-2 and MMP-9 was lower (P＜0.01). Conclusion: SAHA can reduce the expression of MMP-2 and MMP-9 by increasing the expression of RECK protein in animals, thus inhibiting the invasion and metastasis of human breast cancer MCF-7 cell.
[1] 何思怡,李贺,曹毛毛,等. 全球及我国女性乳腺癌疾病负担年龄分布及变化趋势[J].中国肿瘤,2023,32(1):1-7.
[2] Soerjomataram I,Bray F. Planning for tomorrow:global cancer incidence and the role of prevention 2020-2070[J].Nat Rev Clin Oncol,2021,18(10):663-672.
[3] 冯华夷,张晓威,陆航. 辛二酰苯胺异羟肟酸对胃癌MKN-28细胞增殖、凋亡的影响[J].河南医学研究,2021,30(6):961-965.
[4] Mahal K,Kahlen P, Niersack B,et al. 4-(1-Ethyl-4-anisyl-inidazol-5-yl)-M-hydroxycinnamide-A new pleiotropic HDAC inhibit or targeting cancer cell signalling and cytoskeletal organisationp[J].Exp Cell Res,2015,336(2):263-275.
[5] 任凡,高素美. Brachyury上调基质金属蛋白酶(MMPs)与促进肺癌细胞转移的机制[J].国际医药卫生导报,2020,26(20):3067-3070.
[6] 王慧玲,潘小明,黄永鸿. 循环肿瘤细胞与基质金属蛋白酶2基因表达对乳腺癌转移的影响最新研究和进展[J].中国医药指南,2017,15(30):17-18.
[7] Thammineni KL,Thakur GK,Kaur N,et al. Significance of MMP-9 and VEGF-C expression in North Indian women with breast cancer diagnosis[J].Mol Cell Biochem,2019,457(1):93-103.
[8] Sancho-Garnier H,Colonna M. Breast cancer epidemiology[J].Presse Med,2019,48(10):1076-1084.
[9] 王爱红,赵菊梅,王明全. PD-1、CTLA-4和MMP9在伴或不伴淋巴结转移乳腺癌患者外泌体中的表达[J].现代免疫学,2019,39(2):110-114,144.
[10] 柳森森,毛玉宁,张彩勤,等. MMP2在肿瘤侵袭和转移中的调控机制研究[J].中国比较医学杂志,2022,32(3):123-128.
[11] Park HJ,Kim MK,Kim Y,et al. The association of matrix metalloproteinase-8 promoter genotypes in breast cancer[J].Anticancer Res,2019,38(4):2181-2185.
[12] 李朋,徐玲,胡慧,等. 早期乳腺癌患者血清MMP和HER-2胞外结合域的表达及临床意义[J].国际外科学杂志,2018,45(4):238-243.
[13] 吕祥瑞,方卓宁,王孟丽. MMP-9与趋化因子受体7在乳腺癌组织中的表达及临床意义[J].实用癌症杂志,2021,36(3):408-410.
[14] 朱明明,李占全,崔森. MMP-9信号通路调控乳腺癌发展的机制[J].医学信息,2020,33(13):22-25.
[15] 罗俊波,郑瑞锋,王彦威,等. 血清MMP-2、MMP-9和CA15-3水平在乳腺癌中的临床病理学意义及预后价值[J].实用癌症杂志,2019,34(2):195-199.
[16] 王柏琦,陈艳华,蒋丽琴,等. 辛二酰苯胺异羟肟酸对鼻咽癌细胞回复引导半胱氨酸丰富蛋白含kazal基元以及基质金属蛋白酶9表达与活性的影响[J].实用心脑肺血管病杂志,2014,22(6):42-44.
[17] 陈尉. MS-275对骨肉瘤细胞RECK基因表达的影响研究[D].衡阳:南华大学,2014.
