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中华肝脏外科手术学电子杂志 ›› 2024, Vol. 13 ›› Issue (02) : 205 -213. doi: 10.3877/cma.j.issn.2095-3232.2024.02.015

基础研究

DEP结构域蛋白1B在肝细胞癌中的表达及功能
夏辉1, 戴斌1,(), 冉君2, 王威1, 龚昭1, 周程1   
  1. 1. 430000 武汉市第一医院肝胆外科
    2. 430000 武汉,华中科技大学同济医学院附属同济医院放射科
  • 收稿日期:2024-01-03 出版日期:2024-04-10
  • 通信作者: 戴斌
  • 基金资助:
    湖北省自然科学基金(2022CFB980); 武汉市卫生健康委员会医学科研项目(WZ21Q11)

Expression and function of DEP domain-containing protein 1B in hepatocellular carcinoma

Hui Xia1, Bin Dai1,(), Jun Ran2, Wei Wang1, Zhao Gong1, Cheng Zhou1   

  1. 1. Department of Hepatobiliary Surgery, First Hospital of Wuhan, Wuhan 430000, China
    2. Department of Radiology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430000, China
  • Received:2024-01-03 Published:2024-04-10
  • Corresponding author: Bin Dai
引用本文:

夏辉, 戴斌, 冉君, 王威, 龚昭, 周程. DEP结构域蛋白1B在肝细胞癌中的表达及功能[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(02): 205-213.

Hui Xia, Bin Dai, Jun Ran, Wei Wang, Zhao Gong, Cheng Zhou. Expression and function of DEP domain-containing protein 1B in hepatocellular carcinoma[J/OL]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2024, 13(02): 205-213.

目的

探讨DEP结构域蛋白1B(DEPDC1B)在肝细胞癌(肝癌)中的表达及功能。

方法

检索公共癌症数据库(UALCAN、HPA)分析DEPDC1B在肝癌中的表达;从癌症基因组图谱(TCGA)数据库(https://portal.gdc.com)获得肝癌的RNAseq数据(level3)和相应的临床信息,Log-rank用于检验Kaplan-Meier生存分析比较上述两组或多组之间的生存差异;单因素及多因素Cox分析DEPDC1B的预后价值并构建列线图。利用siRNA抑制DEPDC1B表达,通过Transwell小室实验检测细胞侵袭、迁移变化;利用STRING构建DEPDC1B蛋白质相互作用网络(PPI)并分析其在肝癌中潜在作用机制。

结果

肝癌组织中DEPDC1B基因表达量明显高于正常组织(P<0.05)。肝癌DEPDC1B蛋白的阳性表达率为70%,在20种常见癌症的阳性表达率中排名第一。TCGA数据分析显示,DEPDC1B高表达肝癌患者总体生存期和无病生存期均较差(HR=1.673,1.434;P<0.05),其可作为肝癌的独立预后因子且能效预测患者生存率。Transwell小室实验结果显示,siRNA能明显抑制MHCC97-H、Hep3B肝癌细胞DEPDC1Bb表达;下调DEPDC1B表达后,肿瘤细胞的侵袭及迁移能力减弱。PPI网络构建分析显示,DEPDC1B与TsC/mTOR、RTK、RAS/MAPK、PI3K/AKT、雌激素受体、雄激素受体、上皮间质转化、DNA损伤反应、细胞周期和细胞凋亡等肿瘤标志性信号通路密切相关。

结论

DEPDC1B在肝癌中高表达,其高表达与患者预后差相关,下调其表达肝癌细胞侵袭迁移能力下降。

Objective

To investigate the expression and function of DEP domain-containing protein 1B (DEPDC1B) in hepatocellular carcinoma (HCC).

Methods

Public cancer databases (UALCAN, HPA) were searched to analyze the expression profile of DEPDC1B in HCC. RNAseq data (level 3) and corresponding clinical information of HCC were obtained from The Cancer Genome Atlas (TCGA) (https://portal.gdc.com). Kaplan-Meier survival analysis was performed using Log-rank test to compare the survival differences between two groups or among multiple groups. Prognostic value of DEPDC1B was assessed by using univariate and multivariate Cox analysis and the nomogram was established. The expression of DEPDC1B was inhibited by siRNA. The changes of cell invasion and migration were detected by Transwell chamber assay. Protein-protein interaction (PPI) of DEPDC1B was constructed by using STRING and the underlying mechanism in HCC was unraveled.

Results

The expression level of DEPDC1B gene in HCC tissues was significantly higher than that in normal tissues (P<0.05). The positive expression rate of DEPDC1B protein in HCC was 70%, ranking the first among 20 common cancers. TCGA data analysis showed that the overall survival and disease-free survival of HCC patients with high DEPDC1B expression were poor (HR=1.673, 1.434; P<0.05), which could be utilized as an independent prognostic factor of HCC and effectively predict the survival rate of HCC patients. Transwell chamber assay revealed that siRNA could significantly inhibit the expression levels of DEPDC1Bb in MHCC97-H and Hep3B cells. After down-regulating the expression of DEPDC1B, the invasion and migration capabilities of tumor cells were weakened. PPI network showed that DEPDC1B was intimately associated with tumor signaling pathways, such as TsC/mTOR, RTK, RAS/MAPK, PI3K/AKT, estrogen receptor, androgen receptor, epithelial-mesenchymal transition, DNA damage response, cell cycle and apoptosis, etc.

Conclusions

DEPDC1B is highly expressed in HCC. High expression of DEPDC1B is correlated with poor prognosis of HCC patients. Down-regulating the expression of DEPDC1B can weaken the invasion and migration capabilities of HCC cells.

图1 DEPDC1B在正常人体组织样本中基因表达谱注:数据均来自于人类蛋白质图谱(HPA),DEPDC1B为DEP结构域蛋白1B
图2 DEPDC1B在正常人体组织样本中蛋白表达谱注:数据均来自于人类蛋白质图谱(HPA),DEPDC1B为DEP结构域蛋白1B
图3 DEPDC1B mRNA在肝癌组织和正常肝组织中的表达注:数据均来自于UALCAN数据库,DEPDC1B为DEP结构域蛋白1B,※为P<0.05;Transcript per million为每百万条reads的转录本
图4 DEPDC1B蛋白在肝癌组织的表达(免疫组织化法)注:DEPDC1B为DEP结构域蛋白1B
图5 DEPDC1B在肝癌中的预后价值注:a为DEPDC1B在肝癌中的预后价值Kaplan-Meier生存曲线;b为单因素和多因素Cox分析;c为列线图可预测肝癌患者1、3、5年总体生存期;DEPDC1B为DEP结构域蛋白1B
表1 Kaplan-Meier Plotter中肝癌组织DEPDC1B mRNA表达与临床预后的关系
项目 OS DFS
例数 HR P 例数 HR P
性别            
女性 118 1.96(1.11~3.46) 0.019 105 2.82(1.54~5.16) <0.001
男性 246 2.20(1.40~3.44) <0.001 208 1.69(1.08~2.65) 0.020
TNM分期            
1 170 1.78(0.97~3.27) 0.060 153 1.63(0.94~2.81) 0.078
2 83 3.08(1.15~8.23) 0.018 74 1.90(0.79~4.58) 0.140
3 83 2.23(1.23~4.05) 0.001 68 2.69(1.23~5.87) 0.010
4 4     0    
AJCC-T分期            
1 181 1.78(1.00~3.17) 0.048 160 1.67(0.98~2.85) 0.056
2 90 3.15(1.20~8.28) 0.014 79 1.80(0.80~4.08) 0.150
3 78 2.18(1.19~4.01) 0.005 65 2.51(1.17~5.37) 0.015
4 13     6    
组织学分级            
1 55 5.02(1.66~15.13) 0.002 45 3.08(0.70~13.66) 0.120
2 174 2.53(1.31~4.88) 0.004 147 2.13(1.21~3.74) 0.008
3 118 1.98(1.09~3.61) 0.022 106 1.78(1.02~3.10) 0.040
4 12     11    
血管侵犯            
203 1.87(1.12~3.14) 0.016 175 1.44(0.88~2.36) 0.150
微血管 90 1.88(0.79~4.46) 0.150 81 2.63(1.16~5.97) 0.016
大血管 16     14    
索拉非尼 29 6.21(0.77~49.84) 0.054 22 2.48(0.87~7.08) 0.082
饮酒            
115 1.84(0.97~3.50) 0.059 98 2.60(1.41~4.79) 0.002
202 2.00(1.26~3.18) 0.003 182 1.63(1.05~2.55) 0.029
肝炎病毒            
150 1.39(0.07~2.67) 0.310 138 1.27(0.74~2.15) 0.390
167 3.68(1.97~6.87) <0.001 142 3.92(2.01~7.62) <0.001
图6 DEPDC1B对肝癌细胞侵袭迁移能力的影响注:a为siRNA能明显抑制MHCC97-H、Hep3B中DEPDC1B表达水平;b为细胞迁移和侵袭实验,相比于对照组,siRNA处理组中肝癌细胞侵袭迁移能力下降,※为P<0.05;DEPDC1B为DEP结构域蛋白1B
图7 DEPDC1B的PPI网络构建注:DEPDC1B为DEP结构域蛋白1B,PPI为蛋白质-蛋白质相互作用,RHO为RAS同源家族成员,RAC为Ras相关的C3肉毒素底物,CDC42为细胞分裂周期42蛋白
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