HBx对HCC细胞侵袭性的影响及其机理研究
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摘要
原发性肝细胞性肝癌(HCC)是最常见的原发恶性肿瘤之一,死亡率极高,位居肿瘤发病率第五位,肿瘤死亡率第三位。在引发HCC的众多因素中,80%与乙型肝炎病毒(HBV)或/和丙型肝炎病毒(HCV)的慢性感染有关。虽然HBV的致癌机理还不完全清楚,但病毒结构蛋白尤其是HBx蛋白在HBV感染致癌中的作用仍然是科学工作者研究的焦点。本项目在体外研究了HBx对肝癌细胞系侵袭性的影响,并初步探索了NDRG1 (N-myc down-regulated gene 1)调节肿瘤侵袭性的作用机理。
1.首先构建了可表达HBx、NDRG1 cDNA和针对NDRG1 siRNA的重组腺病毒Ad-HBx、Ad-NDRG1和Ad-NDRG1/siRNA,经单斑纯化和扩增后用PCR鉴定,以及对其感染SMMC7721细胞后的Western-blot分析等,都证实成功获得重组腺病毒,并具有良好的感染效果。成功建立了可下调NDRG1表达的稳定转染细胞系AGS/pSuppressor-NDRG1-siRNA和对照AGS/pSuppressor。
2.将包装好的重组腺病毒Ad-HBx、Ad-HBx + Ad-NDRG1、Ad-HBx + Ad-NDRG1/siRNA、Ad-NDRG1、Ad-NDRG1/siRNA和Ad-LacZ瞬时感染SMMC7721细胞,并采用不同方法进行检测分析。(1)Matrigel体外侵袭实验结果表明,HBx可增加细胞的侵袭性;而外源表达的NDRG1则可抑制HBx诱导的细胞侵袭,并且用NDRG1 siRNA降低细胞NDRG1的表达可以增强HBx诱导的侵袭。(2)明胶酶谱法实验结果显示,HBx可上调MMP9的表达,提示HBx可能通过激活MMP9的表达促进细胞的侵袭性;NDRG1不仅可以抑制细胞本身MMP9的表达还可以抑制HBx诱导的MMP-9的表达。(3)Western-blot检测结果显示,HBx和NDRG1-siRNA可显著诱导MT1-MMP的表达,但NDRG1 siRNA并不能增强HBx诱导的MT1-MMP的表达;NDRG1可以显著降低HBx诱导的及细胞本身MT1-MMP的表达;HBx可诱导MMP2的表达,但NDRG1 siRNA和NDRG1都对HBx诱导的MMP2表达有较弱的抑制作用。(4)在AGS细胞中,NDRG1 siRNA可显著诱导细胞的侵袭,并上调MT1-MMP和MMP2的表达;而外源表达NDRG1可抑制NDRG1 siRNA诱导的侵袭。
3.用25 MOI、50 MOI、100 MOI不同剂量的HBx感染SMMC7721细胞,Western-blot检测结果显示NDRG1的抑制表达与HBx呈剂量依赖性,而且HBx还可诱导COX-2的表达,但较弱抑制β-catenin的表达。另外无论在AGS细胞或SMMC7721细胞中NDRG1 siRNA都可以降低COX-2的表达或降低HBx诱导的COX-2表达,且在这两种细胞中都可降低β-catenin的表达。但在SMMC7721细胞中,外源性表达NDRG1也可降低β-catenin的表达。
4.将TOPFlash、Renilla荧光素酶报告载体用脂质体法瞬时共转染感染重组腺病毒Ad-HBx、Ad-HBx + Ad-NDRG1/siRNA、Ad-HBx + Ad-NDRG1、Ad-NDRG1/siRNA、Ad-NDRG1和Ad-LacZ的SMMC7721细胞及稳定转染细胞系AGS/pSuppressor和AGS/pSuppressor-NDRG1-siRNA,测定荧光素酶活性,结果显示HBx可增强TCF/LEF转录活性,而NDRG1 siRNA则可完全抑制HBx激活的TCF/LEF转录活性;而Ad-HBx + Ad-NDRG1、Ad-NDRG1/siRNA和Ad-NDRG1对TCF/LEF的激活有所抑制,但只有Ad-NDRG1可抑制HBx诱导的侵袭性增强;在AGS细胞中,NDRG1 siRNA也抑制了TCF/LEF的转录。因此,Wnt/β-catenin通路对HBx诱导的肿瘤侵袭性增强不起主要作用,但细胞中β-catenin的表达变化有可能与E-cadherin有关,是否影响肿瘤侵袭性有待于进一步研究。
以上研究结果提示,HBx可以增强肿瘤细胞的侵袭性,这种增强作用可能是通过诱导MT1-MMP和MMP9的表达来实现的,并且还可能与β-catenin的表达变化有关。本研究为进一步阐明HBx致HCC的机理以及NDRG1在HCC发生中的作用等提供了新的实验依据。
Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumor, and remains a leading cause of death. It ranks fifth in overall frequency and third in annual mortality rate worldwide. The infection of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) has been identified as a major environmental risk factors to be closely associated with HCC, which account for more than 80% of HCC cases. Although, the underlying mechanism remains unclear, much of the research on HBV hepatocarcinogenesis has been focused on the HBx gene. The aim is to investigate the effect of invasion which HBx protein exert on hepatocellular carcinoma cells and initially explore the mechanism of tumor invasion regulated by NDRG1.
1. Firstly, recombination adenovirus expressing HBx, NDRG1 cDNA and NDRG1 siRNA were successfully constructed. After plaque purification and PCR identification of the amplifying adenovirus, and the Western-blot analysis of SMMC7721 cells transiently infected with them, these results demonstrated the recombinant adenovirus have been successfully produced, and had the favorable infected ability. The stable transfectants cell lines AGS/pSuppressor-NDRG1-siRNA and AGS/pSuppressor have been successfully established which down-regulated NDRG1 and control.
2. After infected SMMC7721 cells with recombinant adenovirus Ad-HBx、Ad-HBx + Ad-NDRG1、Ad-HBx + Ad-NDRG1/siRNA、Ad-NDRG1、Ad-NDRG1/siRNA and Ad-LacZ, the results were analyzed using different experimental methods. (1)Matrigel results showed the invasive ability of cells infected with HBx was improved, and the promoted invasive ability was overall inhibited by exogenous NDRG1, and increased by NDRG1 siRNA. (2)The results of Gelatin Zymograph demonstrated the expression of MMP9 was increased by HBx, but not much higher, and exogenous NDRG1 inhibited intracellular MMP9, as well as inhibited the induced MMP9 expression by HBx to much lower lever. (3)The results of Western-blot showed HBx and NDRG1 siRNA could also induce MT1-MMP expression, but NDRG1 siRNA could not increased the expression of MT1-MMP which induced by HBx; The induced expression of MT1-MMP by HBx was totally inhibited by NDRG1. However, the expression of MMP2 was induced by HBx, which slightly inhibited by NDRG1 and NDRG1-siRNA. (4)NDRG1 siRNA could markly induce the invasion of AGS which inhibited by exogenous NDRG1, meanwhile upregulate the expression of MT1-MMP and MMP2.
3.The results of Western-blot showed the inhibited expression of NDRG1 was depended on the expression of HBx, moreover HBx induced the expression of COX-2 which was decreased by both NDRG1 and NDRG1 siRNA,and weakly inhibited the expression ofβ-catenin in SMMC7721. Additionally, in AGS cells, NDRG1 siRNA inhibited the expression of COX-2 andβ-catenin.
4.After transiently transfected SMMC7721 which infected with Ad-HBx、 Ad-HBx + Ad-NDRG1/siRNA、Ad-HBx + Ad-NDRG1、Ad-NDRG1/siRNA、Ad-NDRG1and Ad-LacZ, and stable transfectants AGS cell lines with TOPFlash and Renilla luciferase reporters, the results showed HBx could active the transcriptional activity of TCF/LEF, which was totally inhibited by NDRG1; moreover, Ad-HBx + Ad-NDRG1、Ad-NDRG1/siRNA and Ad-NDRG1 could also inhibit the transcriptional activity of TCF/LEF in SMMC7721; however, only Ad-NDRG1 inhibited the improved invasion by HBx. In AGS cells, NDRG1 could also inhibit the transcriptional activity of TCF/LEF. These results indicate Wnt/β-catenin pathway doesn’t paly an important role in induced invasion by HBx, there is relationship between the changed expression ofβ-catenin and E-cadherin, so whether the pathway affect the tumor invasion needs more further investigation.
In summary, the tumor invasion was induced by HBx, and totally inhibited by NDRG1. The improved invasion may achieve through the expression MT1-MMP and MMP9 induced by HBx,and the induced expression of MT1-MMP and MMP9 could be inhibited by NDRG1, there exists the possibility between improved invasion and changed expression ofβ-catenin. The study provides a new experimental basis to further elucidate the roles of HBx and NDRG1 in pathogenesis of HCC.
1.首先构建了可表达HBx、NDRG1 cDNA和针对NDRG1 siRNA的重组腺病毒Ad-HBx、Ad-NDRG1和Ad-NDRG1/siRNA,经单斑纯化和扩增后用PCR鉴定,以及对其感染SMMC7721细胞后的Western-blot分析等,都证实成功获得重组腺病毒,并具有良好的感染效果。成功建立了可下调NDRG1表达的稳定转染细胞系AGS/pSuppressor-NDRG1-siRNA和对照AGS/pSuppressor。
2.将包装好的重组腺病毒Ad-HBx、Ad-HBx + Ad-NDRG1、Ad-HBx + Ad-NDRG1/siRNA、Ad-NDRG1、Ad-NDRG1/siRNA和Ad-LacZ瞬时感染SMMC7721细胞,并采用不同方法进行检测分析。(1)Matrigel体外侵袭实验结果表明,HBx可增加细胞的侵袭性;而外源表达的NDRG1则可抑制HBx诱导的细胞侵袭,并且用NDRG1 siRNA降低细胞NDRG1的表达可以增强HBx诱导的侵袭。(2)明胶酶谱法实验结果显示,HBx可上调MMP9的表达,提示HBx可能通过激活MMP9的表达促进细胞的侵袭性;NDRG1不仅可以抑制细胞本身MMP9的表达还可以抑制HBx诱导的MMP-9的表达。(3)Western-blot检测结果显示,HBx和NDRG1-siRNA可显著诱导MT1-MMP的表达,但NDRG1 siRNA并不能增强HBx诱导的MT1-MMP的表达;NDRG1可以显著降低HBx诱导的及细胞本身MT1-MMP的表达;HBx可诱导MMP2的表达,但NDRG1 siRNA和NDRG1都对HBx诱导的MMP2表达有较弱的抑制作用。(4)在AGS细胞中,NDRG1 siRNA可显著诱导细胞的侵袭,并上调MT1-MMP和MMP2的表达;而外源表达NDRG1可抑制NDRG1 siRNA诱导的侵袭。
3.用25 MOI、50 MOI、100 MOI不同剂量的HBx感染SMMC7721细胞,Western-blot检测结果显示NDRG1的抑制表达与HBx呈剂量依赖性,而且HBx还可诱导COX-2的表达,但较弱抑制β-catenin的表达。另外无论在AGS细胞或SMMC7721细胞中NDRG1 siRNA都可以降低COX-2的表达或降低HBx诱导的COX-2表达,且在这两种细胞中都可降低β-catenin的表达。但在SMMC7721细胞中,外源性表达NDRG1也可降低β-catenin的表达。
4.将TOPFlash、Renilla荧光素酶报告载体用脂质体法瞬时共转染感染重组腺病毒Ad-HBx、Ad-HBx + Ad-NDRG1/siRNA、Ad-HBx + Ad-NDRG1、Ad-NDRG1/siRNA、Ad-NDRG1和Ad-LacZ的SMMC7721细胞及稳定转染细胞系AGS/pSuppressor和AGS/pSuppressor-NDRG1-siRNA,测定荧光素酶活性,结果显示HBx可增强TCF/LEF转录活性,而NDRG1 siRNA则可完全抑制HBx激活的TCF/LEF转录活性;而Ad-HBx + Ad-NDRG1、Ad-NDRG1/siRNA和Ad-NDRG1对TCF/LEF的激活有所抑制,但只有Ad-NDRG1可抑制HBx诱导的侵袭性增强;在AGS细胞中,NDRG1 siRNA也抑制了TCF/LEF的转录。因此,Wnt/β-catenin通路对HBx诱导的肿瘤侵袭性增强不起主要作用,但细胞中β-catenin的表达变化有可能与E-cadherin有关,是否影响肿瘤侵袭性有待于进一步研究。
以上研究结果提示,HBx可以增强肿瘤细胞的侵袭性,这种增强作用可能是通过诱导MT1-MMP和MMP9的表达来实现的,并且还可能与β-catenin的表达变化有关。本研究为进一步阐明HBx致HCC的机理以及NDRG1在HCC发生中的作用等提供了新的实验依据。
Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumor, and remains a leading cause of death. It ranks fifth in overall frequency and third in annual mortality rate worldwide. The infection of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) has been identified as a major environmental risk factors to be closely associated with HCC, which account for more than 80% of HCC cases. Although, the underlying mechanism remains unclear, much of the research on HBV hepatocarcinogenesis has been focused on the HBx gene. The aim is to investigate the effect of invasion which HBx protein exert on hepatocellular carcinoma cells and initially explore the mechanism of tumor invasion regulated by NDRG1.
1. Firstly, recombination adenovirus expressing HBx, NDRG1 cDNA and NDRG1 siRNA were successfully constructed. After plaque purification and PCR identification of the amplifying adenovirus, and the Western-blot analysis of SMMC7721 cells transiently infected with them, these results demonstrated the recombinant adenovirus have been successfully produced, and had the favorable infected ability. The stable transfectants cell lines AGS/pSuppressor-NDRG1-siRNA and AGS/pSuppressor have been successfully established which down-regulated NDRG1 and control.
2. After infected SMMC7721 cells with recombinant adenovirus Ad-HBx、Ad-HBx + Ad-NDRG1、Ad-HBx + Ad-NDRG1/siRNA、Ad-NDRG1、Ad-NDRG1/siRNA and Ad-LacZ, the results were analyzed using different experimental methods. (1)Matrigel results showed the invasive ability of cells infected with HBx was improved, and the promoted invasive ability was overall inhibited by exogenous NDRG1, and increased by NDRG1 siRNA. (2)The results of Gelatin Zymograph demonstrated the expression of MMP9 was increased by HBx, but not much higher, and exogenous NDRG1 inhibited intracellular MMP9, as well as inhibited the induced MMP9 expression by HBx to much lower lever. (3)The results of Western-blot showed HBx and NDRG1 siRNA could also induce MT1-MMP expression, but NDRG1 siRNA could not increased the expression of MT1-MMP which induced by HBx; The induced expression of MT1-MMP by HBx was totally inhibited by NDRG1. However, the expression of MMP2 was induced by HBx, which slightly inhibited by NDRG1 and NDRG1-siRNA. (4)NDRG1 siRNA could markly induce the invasion of AGS which inhibited by exogenous NDRG1, meanwhile upregulate the expression of MT1-MMP and MMP2.
3.The results of Western-blot showed the inhibited expression of NDRG1 was depended on the expression of HBx, moreover HBx induced the expression of COX-2 which was decreased by both NDRG1 and NDRG1 siRNA,and weakly inhibited the expression ofβ-catenin in SMMC7721. Additionally, in AGS cells, NDRG1 siRNA inhibited the expression of COX-2 andβ-catenin.
4.After transiently transfected SMMC7721 which infected with Ad-HBx、 Ad-HBx + Ad-NDRG1/siRNA、Ad-HBx + Ad-NDRG1、Ad-NDRG1/siRNA、Ad-NDRG1and Ad-LacZ, and stable transfectants AGS cell lines with TOPFlash and Renilla luciferase reporters, the results showed HBx could active the transcriptional activity of TCF/LEF, which was totally inhibited by NDRG1; moreover, Ad-HBx + Ad-NDRG1、Ad-NDRG1/siRNA and Ad-NDRG1 could also inhibit the transcriptional activity of TCF/LEF in SMMC7721; however, only Ad-NDRG1 inhibited the improved invasion by HBx. In AGS cells, NDRG1 could also inhibit the transcriptional activity of TCF/LEF. These results indicate Wnt/β-catenin pathway doesn’t paly an important role in induced invasion by HBx, there is relationship between the changed expression ofβ-catenin and E-cadherin, so whether the pathway affect the tumor invasion needs more further investigation.
In summary, the tumor invasion was induced by HBx, and totally inhibited by NDRG1. The improved invasion may achieve through the expression MT1-MMP and MMP9 induced by HBx,and the induced expression of MT1-MMP and MMP9 could be inhibited by NDRG1, there exists the possibility between improved invasion and changed expression ofβ-catenin. The study provides a new experimental basis to further elucidate the roles of HBx and NDRG1 in pathogenesis of HCC.
引文
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