苯胺嘧啶衍生物X-9通过下调整合素β1表达抑制肝细胞癌迁移侵袭  

Aniline Pyrimidine Derivative X-9 Inhibits the Migration and Invasion of Hepatocellular Carcinoma by Down-regulating the Expression of Integrin β1

作　　者：周彤彤 段继燕 吴志贤 徐剑文 陈坤 曾锦章[1] 侯培锋[3,4,5] 刘杰 ZHOU Tong-Tong;DUAN Ji-Yan;WU Zhi-Xian;XU Jian-Wen;CHEN Kun;ZENG Jin-Zhang;HOU Pei-Feng;LIU Jie(Key Laboratory of Innovative Drug Target Research of Fujian Province,School of Pharmaceutical Sciences,Xiamen University,Xiamen 361102,Fujian,China; Department of Hepatobiliary Disease,Fuzhou General Hospital,Fuzhou 350025,China; Department of Medical Oncology,Fujian Medical University Union Hospital,Fuzhou 350000,China; Fujian Medical University Stem Cell Research Institute,Fuzhou 350000,China; Key Laboratory of Translational Cancer Medicine of Fujian Province,Fuzhou 350000,China)

机构地区：[1]厦门大学药学院福建省靶点药物重点实验室,福建厦门361102 [2]中国人民解放军福州总医院肝胆内科,福州350025 [3]福建医科大学协和医院肿瘤内科,福州350000 [4]福建医科大学干细胞研究中心,福州350000 [5]福建省转化肿瘤医学重点实验室,福州350000

出　　处：《中国生物化学与分子生物学报》2020年第2期165-173,共9页Chinese Journal of Biochemistry and Molecular Biology

基　　金：福建省自然科学基金(No.2016J05087,No.2017J01201);福建省卫计委医疗创新项目(No.2015-CXB-15)资助。

摘　　要：整合素在许多肿瘤细胞中高表达,并且参与肿瘤细胞的侵袭转移。在肝细胞癌中,整合素β1被报导高表达,并促进肿瘤细胞的侵袭。目前,对于整合素的表达调控癌细胞机制以及干预其表达进而抑制肿瘤细胞转移的研究较少。本研究探讨利用小分子化合物抑制整合素表达来抑制肿瘤细胞迁移和侵袭的可能。首先,对临床肝癌细胞患者癌组织和癌旁组织中的整合素β1的表达进行检测,发现其在癌组织中的表达显著高于癌旁组织(P<0.05)。对TCGA肿瘤数据库的生物信息学分析结果同样显示,整合素β1的高表达与肝癌的分期(P=0.019)和预后(P=0.013)相关。通过筛选发现,苯胺嘧啶衍生物X-9可以抑制肝癌细胞中整合素β1的mRNA和蛋白质的表达(P<0.01)。细胞划痕愈合实验和细胞穿孔实验结果显示,苯胺嘧啶衍生物X-9能够抑制肝癌细胞的迁移和侵袭(P<0.01)。进一步的研究证实,在肝癌细胞中外源表达整合素β1可以逆转X-9对肝癌细胞迁移和侵袭的抑制;而在敲低整合素β1的细胞中,X-9对细胞的迁移和侵袭的抑制被消除。因此,鉴定出苯胺嘧啶衍生物X-9可以通过下调整合素β1表达,进而抑制肝癌细胞的迁移和侵袭。Integrins are highly expressed in many tumors and involved in tumor invasion and metastasis. In hepatocellular carcinoma(HCC), overexpression of integrin β1 is reported to promote tumor cell invasion. To date, studies on the mechanism of regulation and interference of integrin expression to inhibit cancer metastasis is still scanty. This study investigates the possibility of inhibiting tumor cell migration and invasion by inhibiting integrin expression with small molecule compounds. Firstly, we examined the expression of integrin β1 in tumor and para-tumor tissues from clinical HCC patients and found that expression of integrin β1 in tumor tissues is significantly higher than that in para-tumor tissues. The analysis results of correlation between integrin β1 and tumor stage and over survival rate of LIHC data set from TCGA database also showed that high expression of integrin β1 was positive correlated with tumor stage(P=0.019) and over survival rate(P=0.013). Then we identified aniline pyrimidine derivative X-9 down-regulated integrin β1 at both mRNA and protein levels. The wound healing and transwell invasion assay showed that aniline pyrimidine derivative X-9 inhibited hepatocellular carcinoma migration and invasion(P<0.01). Further studies indicated that expression of exogenous integrin β1 could reverse the inhibition of hepatocellular carcinoma migration and invasion induced by aniline pyrimidine derivative X-9;and the inhibition of cell migration and invasion induced by aniline pyrimidine derivative X-9 was eliminated in cells with integrin β1 knock-down. Thus, we identified that aniline pyrimidine derivative X-9 inhibited hepatocellular carcinoma migration and invasion via down-regulating integrin β1 expression.

关 键 词：整合素Β1 苯胺嘧啶衍生物 肝细胞癌 癌细胞迁移 癌细胞侵袭 

分 类 号：Q966[生物学—昆虫学]