miRNAs在原发性肝癌中的表达及临床意义分析
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摘要
目的:验证miRNAs在肝癌及癌旁组织样本中的表达,并探讨miRNAs表达水平与2年乙肝相关性肝癌复发转移的相关性。方法:采用实时荧光定量逆转录聚合酶链式反应(real-time PCR)检测miR-21、miR-151、miR-96及miR-198在30例肝癌及癌旁组织样本中的表达情况,并分析miRNAs的表达水平与临床病理特征的关系。结果:与癌旁组织相比,miR-21、miR-96及miR-151肝癌组织较癌旁组织中表达上调,占总体样本的76.7%、70%、66.7%;而miR-198在肝癌组织中表达下调,占总体样本的66.7%。通过对临床资料的分析,本研究发现miRNAs在肝癌组织中的表达差异与肝癌患者肿瘤数目、分化程度、TNM分期、门静脉癌栓及2年复发转移等密切相关(P<0.05)。结论:miRNAs在肝癌及癌旁组织样本中的表达水平存在明显差异,并与肝癌的恶性表型显著相关;miR-21、miR-151和miR-96能促进肝癌的侵袭转移,而miR-198能抑制肝癌的侵袭转移;miRNAs的共同作用可影响患者的预后。
Objective: To verify the expression of miRNAs of hepatocellular carcinoma(HCC) and adjacent tissue samples,to investigate the correlation between miRNAs expression and recurrence and metastasis of liver cancer-associated with HBV in 2 years. Methods:To detect the expression of miR-21,miR-151,miR-96 and miR-198 in 30 cases of hepatocellular carcinoma and paracancerous tissue samples by real-time quantitative reverse transcriptase polymerase chain reaction,and analyze the relationship between the expression level of miRNAs and clinical pathological features. Results: Compared with the adjacent tissues,the expression of miR-21,miR-96 and miR-151 in hepatocellular carcinoma tissues was higher than adjacent tissues,accounting for 76. 7%,70%,66. 7% of the overall sample;and the expression of miR-198 in hepatocellular carcinoma tissues was lower than adjacent tissues,accounting for 66. 7% of the overall sample. Through the analysis of clinical data,we found that the expression of miRNAs in HCC tissues was closely related to the number of tumor,differentiation,TNM stage,portal vein tumor thrombus and 2 year recurrence and metastasis(P < 0. 05). Conclusion: There are obvious differences in the expression level of miRNAs in HCC tissue samples,and was associated with the malignant phenotype of hepatocellular carcinoma; miR-21,miR-151 and miR-96 can promote the invasion and metastasis of HCC,and miR-198 can inhibit the invasion and metastasis of HCC,interaction of miRNAs can affect the prognosis of patients.
Objective: To verify the expression of miRNAs of hepatocellular carcinoma(HCC) and adjacent tissue samples,to investigate the correlation between miRNAs expression and recurrence and metastasis of liver cancer-associated with HBV in 2 years. Methods:To detect the expression of miR-21,miR-151,miR-96 and miR-198 in 30 cases of hepatocellular carcinoma and paracancerous tissue samples by real-time quantitative reverse transcriptase polymerase chain reaction,and analyze the relationship between the expression level of miRNAs and clinical pathological features. Results: Compared with the adjacent tissues,the expression of miR-21,miR-96 and miR-151 in hepatocellular carcinoma tissues was higher than adjacent tissues,accounting for 76. 7%,70%,66. 7% of the overall sample;and the expression of miR-198 in hepatocellular carcinoma tissues was lower than adjacent tissues,accounting for 66. 7% of the overall sample. Through the analysis of clinical data,we found that the expression of miRNAs in HCC tissues was closely related to the number of tumor,differentiation,TNM stage,portal vein tumor thrombus and 2 year recurrence and metastasis(P < 0. 05). Conclusion: There are obvious differences in the expression level of miRNAs in HCC tissue samples,and was associated with the malignant phenotype of hepatocellular carcinoma; miR-21,miR-151 and miR-96 can promote the invasion and metastasis of HCC,and miR-198 can inhibit the invasion and metastasis of HCC,interaction of miRNAs can affect the prognosis of patients.
引文
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[24]Luedde T.MicroRNA-151 and its hosting gene FAK(focal adhesion kinase)regulate tumor cell migration and spreading of hepatocellular carcinoma[J].Hepatology,2010,52(3):1164-1166.
[25]何祥火,梁琳慧,丁洁,等.非编码小RNA在肝癌发生中的作用及机制研究进展[J].上海交通大学学报(医学版),2012,32(9):40.
[26]Chiyomaru T,Yamamura S,Zaman MS,et al.Genistein suppresses prostate cancer growth through inhibition of oncogenic microRNA-151[J].PLOS One,2012,7(8):e43812.
[27]Elfimova N,Sievers E,Eischeid H,et al.Control of mitogenic and motogenic pathways by miR-198,diminishing hepatoma cell growth and migration[J].Biochim Biophys Acta,2013,1833(5):1190-1198.
[28]Huang WT,Wang HL,Yang H,et al.Lower expressed miR-198 and its potential targets in hepatocellular carcinoma:a clinicopathological and in silico study[J].Onco Targets Ther,2016,22(9):5163-5180.
[29]Yang J,Zhao H,Xin Y,et al.MicroRNA-198 inhibits proliferation and induces apoptosis of lung cancer cells via targeting FGFR1[J].J Cell Biochem,2014,115(5):987-995.
[2]沈艺南,何海冠,王舟翀,等.乙肝相关肝细胞癌中HBx蛋白的作用机制[J].肝胆外科杂志,2015,78(4):389-397.
[3]Tang ZY.Hepatocellular carcinoma-cause,treatment and metastasis[J].World Gastroenterol,2001,7(4):445-454.
[4]徐国斌,易广雄,熊斌,等.原发性肝癌术后6个月内早期复发转移的介入治疗[J].介入放射学杂志,2013,22(4):325-327.
[5]Bartel DP.Micro NAs:target recognition and regulatory functions[J].Cell,2009,136(2):215-233.
[6]Lund E,Güttinger S,Calado A,et al.Nuclear export of microRNA precursors[J].Science,2004,303(5654):95-98.
[7]Lai KW,Koh KX,Loh M,et al.Micro NA-130b regulates the tumour suppressor RUNX3 in gastric cancer[J].Eur J Cancer,2010,46(8):1456-1463.
[8]项涛,雷慧.腹水miRNA-497、miRNA-936测定在胃癌性腹水腹腔化疗联合全身靶向治疗中的意义[J].肿瘤基础与临床,2013,26(2):142-144.
[9]Becker N,Lockwood CM.Pre-analytical variables in miRNA analysis[J].Clin Biochem,2013,46:861-868.
[10]Takahashi RU,Miyazaki H,Ochiya T.The role of microRNAs in the regulation of cancer stem cells[J].Front Genet,2014,4:295-231.
[11]方国强,吴炳礼,李恩民,等.MicroRNA-21与肿瘤[J].癌变·畸变·突变,2010,22(1):68-74.
[12]Li Y,Di C,Li W,et al.Oncomirs miRNA-221/222 and Tumor Suppressors miRNA-199a/195 Are Crucial miRNAs in Liver Cancer:A Systematic Analysis[J].Dig Dis Sci,2016,61(8):2315-2327.
[13]Meng F,Henson R,Wehbe-Janek H.MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cance[J].Gastroenterology,2007,133:647-658.
[14]Liu C,Yu J,Yu S.MicroRNA-21 acts as an oncomir through multiple targets in human hepatocellular carcinom[J].J Hepatol,2010,53(1):98-107.
[15]Liu WH,Ren LN,Wang X,et al.Combination of exosomes and circulating microRNAs may serve as a promising tumor marker complementary to alphafetoprotein for early-stage hepatocellular carcinoma diagnosis in rats[J].J Cancer Res Clin Oncol,2015,141(10):1767-1778.
[16]Devulapally R,Foygel K,Sekar TV,et al.Gemcitabine and Antisense-microRNA Co-encapsulated PLGA-PEG Polymer Nanoparticles for Hepatocellular Carcinoma Therapy[J].ACS Appl Mater Interfaces,2016,14,8(49):33412-33422.
[17]Piluso A,Gragnani L,Fognani E,et al.Deregulation of microRNA expression in peripheral blood mononuclear cells from patients with HCV-related malignancies[J].Hepatol Int,2015,9(4):586-593.
[18]Huang CS,Yu,Cui H,et al.Increased expression of miR-21 predicts poor prognosis in patients with hepatocellular carcinoma[J].Int J Clin Exp Pathol,2015,8(6):7234-7238.
[19]Wu L,Pu X,Wang Q,et al.miR-96 induces cisplatin chemoresistance in non-small cell lung cancer cells by downregulating SAMD9[J].Oncol Lett,2016,11(2):945-952.
[20]Zhang W,Qian P,Zhang X,et al.Autocrine/Paracrine Human Growth Hormone-stimulated MicroRNA 96-182-183 Cluster Promotes Epithelial-Mesenchymal Transition and Invasion in Breast Cancer[J].J Biol Chem,2015,290(22):13812-13829.
[21]Gao F,Wang W.MicroRNA-96 promotes the proliferation of colorectal cancer cells and targets tumor protein p53 inducible nuclear protein 1,forkhead box protein O1(FOXO1)and FOXO3a[J].Mol Med Rep,2015,11(2):1200-1206.
[22]Chen RX,Xia YH,Xue TC,et al.Suppression of microRNA-96 expression inhibits the invasion of hepatocellular carcinoma cells[J].Mol Med Rep,2012,5(3):800-804.
[23]Chen Y,Dong X,Yu D,et al.Serum miR-96 is a promising biomarker for hepatocellular carcinoma in patients with chronic hepatitis B virus infection[J].Int J Clin Exp Med,2015,15,8(10):18462-18468.
[24]Luedde T.MicroRNA-151 and its hosting gene FAK(focal adhesion kinase)regulate tumor cell migration and spreading of hepatocellular carcinoma[J].Hepatology,2010,52(3):1164-1166.
[25]何祥火,梁琳慧,丁洁,等.非编码小RNA在肝癌发生中的作用及机制研究进展[J].上海交通大学学报(医学版),2012,32(9):40.
[26]Chiyomaru T,Yamamura S,Zaman MS,et al.Genistein suppresses prostate cancer growth through inhibition of oncogenic microRNA-151[J].PLOS One,2012,7(8):e43812.
[27]Elfimova N,Sievers E,Eischeid H,et al.Control of mitogenic and motogenic pathways by miR-198,diminishing hepatoma cell growth and migration[J].Biochim Biophys Acta,2013,1833(5):1190-1198.
[28]Huang WT,Wang HL,Yang H,et al.Lower expressed miR-198 and its potential targets in hepatocellular carcinoma:a clinicopathological and in silico study[J].Onco Targets Ther,2016,22(9):5163-5180.
[29]Yang J,Zhao H,Xin Y,et al.MicroRNA-198 inhibits proliferation and induces apoptosis of lung cancer cells via targeting FGFR1[J].J Cell Biochem,2014,115(5):987-995.