HDAC2在肝细胞肝癌中对MMP9表达的影响
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摘要
目的:明确组蛋白去乙酰化酶2(HDAC2)在肝细胞肝癌(HCC)中对基质金属蛋白酶9(MMP9)表达的影响。方法:利用mRNA表达谱芯片数据进行统计分析,确定HDAC2和MMP9的mRNA在HCC组织中的表达情况及相关性;实时定量PCR检测HDAC2过表达对MMP9转录的影响;蛋白免疫印迹检测HDAC2过表达对MMP9蛋白表达的影响。结果:HDAC2和MMP9的mRNA在HCC肿瘤组织中均表达升高并呈正相关性;在Hep G2细胞中,HDAC2促进MMP9的转录及蛋白表达。结论:HDAC2在HCC中促进MMP9的表达,可能在HCC转移过程中发挥作用。
Objective: To evaluate the impact of HDAC2 on MMP9 expression in hepatocellular carcinoma( HCC). Methods: The expressions of HDAC2 and MMP9 in HCC tissues were evaluated with microarray data,and their correlation was analyzed. Real-time PCR was performed to detect the effect of HDAC2 overexpression on mRNA level of MMP9. Western Blot was used to detect the effect of HDAC2 overexpression on protein level of MMP9. Results: Both HDAC2 and MMP9 were higher expressed in HCC tissues,compared with that in normal liver tissues.There was a positive correlation between HDAC2 expression and MMP9 expression. In Hep G2 cells,overexpression of HDAC2 increased both mRNA and protein expression of MMP9. Conclusion: HDAC2 promotes MMP9 expression in HCC,which may be involved in tumor metastasis of HCC.
Objective: To evaluate the impact of HDAC2 on MMP9 expression in hepatocellular carcinoma( HCC). Methods: The expressions of HDAC2 and MMP9 in HCC tissues were evaluated with microarray data,and their correlation was analyzed. Real-time PCR was performed to detect the effect of HDAC2 overexpression on mRNA level of MMP9. Western Blot was used to detect the effect of HDAC2 overexpression on protein level of MMP9. Results: Both HDAC2 and MMP9 were higher expressed in HCC tissues,compared with that in normal liver tissues.There was a positive correlation between HDAC2 expression and MMP9 expression. In Hep G2 cells,overexpression of HDAC2 increased both mRNA and protein expression of MMP9. Conclusion: HDAC2 promotes MMP9 expression in HCC,which may be involved in tumor metastasis of HCC.
引文
[1]Drazic A,Myklebust LM,Ree R,et al.The world of protein acetylation[J].Biochim Biophys Acta,2016,1864(10):1372-1401.
[2]Ler SY,Leung CH,Khin LW,et al.HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population[J].Oncol Rep,2015,34(5):2238-2250.
[3]Wurmbach E,Chen YB,Khitrov G,et al.Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma[J].Hepatology,2007,45(4):938-947.
[4]Bruix J,Boix L,Sala M,et al.Focus on hepatocellular carcinoma[J].Cancer Cell,2004,(3):215-219.
[5]Chen WQ,Zheng RS,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[6]Lv GS,Chen L,Wang HY.Research progress and prospect of liver cancer in China[J].Chinese Bulletin of Life Sciences,2015,27(3):237-248.[吕桂帅,陈磊,王红阳.我国肝癌研究的现状与前景[J].生命科学,2015,27(3):237-248.]
[7]Van Dyke.Lysine deacetylase(KDAC)regulatory pathways:An alternative approach to selective modulation[J].Chem Med Chem,2014,9(3):511-522.
[8]Mutze K,Langer R,Becker K,et al.Histone deacetylase(HDAC)1and 2 expression and chemotherapy in gastric cancer[J].Ann Surg Oncol,2010,17(12):3336-3343.
[9]Weichert W,Roske A,Gekeler V,et al.Histone deacetylases 1,2and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy[J].Br J Cancer,2008,98(3):604-610.
[10]Hulsurkar M,Li Z,Zhang Y,et al.Beta-adrenergic signaling promotes tumor angiogenesis and prostate cancer progression through HDAC2-mediated suppression of thrombospondin-1[J].Oncogene,2017,36(11):1525-1536.
[11]Zhao H,Yu Z,Zhao L,et al.HDAC2 overexpression is a poor prognostic factor of breast cancer patients with increased multidrug resistance-associated protein expression who received anthracyclines therapy[J].Jpn J Clin Oncol,2016,46(10):893-902.
[12]Kramer OH.HDAC2:A critical factor in health and disease[J].Trends Pharmacol Sci,2009,30(12):647-655.
[13]Muller BM,Jana L,Kasajima A,et al.Differential expression of histone deacetylases HDAC1,2 and 3 in human breast canceroverexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression[J].BMC Cancer,2013,13:215.
[14]Buurman R,Gurlevik E,Schaffer V,et al.Histone deacetylases activate hepatocyte growth factor signaling by repressing microR-NA-449 in hepatocellular carcinoma cells[J].Gastroenterology,2012,143(3):811-820.
[15]Noh JH,Jung KH,Kim JK,et al.Aberrant regulation of HDAC2mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1/S cell cycle proteins[J].PLo S One,2011,6(11):e28103.
[16]Lee YH,Seo D,Choi KJ,et al.Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2[J].Cancer Res,2014,74(17):4752-4761.
[17]Wang F,Qi Y,Li X,et al.HDAC inhibitor trichostatin A suppresses esophageal squamous cell carcinoma metastasis through HADC2 reduced MMP-2/9[J].Clin Invest Med,2013,36(2):E87-E94.
[18]Song C,Zhu S,Wu C,et al.Histone deacetylase(HDAC)10 suppresses cervical cancer metastasis through inhibition of matrix metalloproteinase(MMP)2 and 9 expression[J].J Biol Chem,2013,288(39):28021-28033.
[2]Ler SY,Leung CH,Khin LW,et al.HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population[J].Oncol Rep,2015,34(5):2238-2250.
[3]Wurmbach E,Chen YB,Khitrov G,et al.Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma[J].Hepatology,2007,45(4):938-947.
[4]Bruix J,Boix L,Sala M,et al.Focus on hepatocellular carcinoma[J].Cancer Cell,2004,(3):215-219.
[5]Chen WQ,Zheng RS,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[6]Lv GS,Chen L,Wang HY.Research progress and prospect of liver cancer in China[J].Chinese Bulletin of Life Sciences,2015,27(3):237-248.[吕桂帅,陈磊,王红阳.我国肝癌研究的现状与前景[J].生命科学,2015,27(3):237-248.]
[7]Van Dyke.Lysine deacetylase(KDAC)regulatory pathways:An alternative approach to selective modulation[J].Chem Med Chem,2014,9(3):511-522.
[8]Mutze K,Langer R,Becker K,et al.Histone deacetylase(HDAC)1and 2 expression and chemotherapy in gastric cancer[J].Ann Surg Oncol,2010,17(12):3336-3343.
[9]Weichert W,Roske A,Gekeler V,et al.Histone deacetylases 1,2and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy[J].Br J Cancer,2008,98(3):604-610.
[10]Hulsurkar M,Li Z,Zhang Y,et al.Beta-adrenergic signaling promotes tumor angiogenesis and prostate cancer progression through HDAC2-mediated suppression of thrombospondin-1[J].Oncogene,2017,36(11):1525-1536.
[11]Zhao H,Yu Z,Zhao L,et al.HDAC2 overexpression is a poor prognostic factor of breast cancer patients with increased multidrug resistance-associated protein expression who received anthracyclines therapy[J].Jpn J Clin Oncol,2016,46(10):893-902.
[12]Kramer OH.HDAC2:A critical factor in health and disease[J].Trends Pharmacol Sci,2009,30(12):647-655.
[13]Muller BM,Jana L,Kasajima A,et al.Differential expression of histone deacetylases HDAC1,2 and 3 in human breast canceroverexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression[J].BMC Cancer,2013,13:215.
[14]Buurman R,Gurlevik E,Schaffer V,et al.Histone deacetylases activate hepatocyte growth factor signaling by repressing microR-NA-449 in hepatocellular carcinoma cells[J].Gastroenterology,2012,143(3):811-820.
[15]Noh JH,Jung KH,Kim JK,et al.Aberrant regulation of HDAC2mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1/S cell cycle proteins[J].PLo S One,2011,6(11):e28103.
[16]Lee YH,Seo D,Choi KJ,et al.Antitumor effects in hepatocarcinoma of isoform-selective inhibition of HDAC2[J].Cancer Res,2014,74(17):4752-4761.
[17]Wang F,Qi Y,Li X,et al.HDAC inhibitor trichostatin A suppresses esophageal squamous cell carcinoma metastasis through HADC2 reduced MMP-2/9[J].Clin Invest Med,2013,36(2):E87-E94.
[18]Song C,Zhu S,Wu C,et al.Histone deacetylase(HDAC)10 suppresses cervical cancer metastasis through inhibition of matrix metalloproteinase(MMP)2 and 9 expression[J].J Biol Chem,2013,288(39):28021-28033.