DEN和NMOR联合诱导F344大鼠肝癌形成过程中SERPINB5的表达变化
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摘要
目的观察化学法诱导F344大鼠肝细胞癌(hepatocellular carcinoma,HCC)形成过程中肝组织内SERPINB5蛋白的表达变化,探讨其与HCC发生、发展的关系,为肝癌早期诊断和治疗提供新的思路。方法采用复合化学法诱导50只F344雄性大鼠建立HCC模型(化学诱癌组),对照组为30只F344雄性大鼠。观察两组大鼠生长状态,每隔4周随机处死观察组10只,对照组6只大鼠,观察肝脏的肉眼和组织形态学改变,并采用免疫组化法检测肝组织内SERPINB5蛋白的表达情况。结果复合化学法诱导16周能成功诱导大鼠HCC。与对照组相比,诱导不同时间的化学诱癌组的大鼠肝组织形态学和SERPINB5蛋白的表达出现不同的改变。自第4周起,两组大鼠肝组织形态学出现差异。随着化学诱导时间的延长,化学诱癌组大鼠肝组织形态学出现不同的特征改变,第12周时,呈现典型的肝炎表现,第16周时,呈现典型的肝硬化表现,并伴有癌细胞微浸润,第20周时,癌细胞异型性更加明显,可见癌细胞大量浸润。第16周时,SERPINB5蛋白的表达量开始明显下降,差异有统计学意义(P<0.05),第20周时,SERPINB5的表达明显降低(P<0.05),且与诱癌第16周比较,差异亦有统计学意义(P<0.05)。结论在大鼠肝脏组织中,SERPINB5蛋白表达呈下降趋势,表明SERPINB5与HCC的发生、发展有密切关系;SERPINB5可能是肝癌早期诊断的新分子标记及其治疗的新靶点。
Objective To evaluate the expression of SERPINB5 in the process of hepatocellular carcinogenesis in chemical-induced F344 rat(hepatocellular carcinoma,HCC)model so as to explore the relationship of SERPINB5 with the occurrence and development of HCC.Methods We used 50 male F344 rats to induce HCC model.They were treated with diethylnirtosamine and N-nitrosomorpholine.Another 30 male F344 rats were used as controls.After 10 rats in model group and 6 in control group were sacrificed every 4 weeks,the pathological changes were evaluated by H&E staining.The expression of SERPINB5 was detected by immunohistochemistry.Results F344 rats liver cancer was confirmed16 and 20 weeks after HCC induction by diethylnirtosamine and N-nitrosomorpholine.Moreover,the morphological differences between HCC-induced and control groups were observed from week 4 induction.With the extension of chemical induction,the typical manifestations of hepatitis were shown at week12.Typical cirrhosis accompanied by micro-invasion of cancer cells was seen at week 16.At week 20,atypia of cancer cells was more obvious and the invasion of cancer cells was large.The expression of SERPINB5 was significantly decreased(P <0.05)compared with that at week 16 of cancer induction.Conclusion The expression of SERPINB5 is down-regulated in rat liver tissue,suggesting that SERPINB5 is closely related to the occurrence and development of liver carcinoma.Our findings provide new ideas for the early diagnosis and treatment of HCC.
Objective To evaluate the expression of SERPINB5 in the process of hepatocellular carcinogenesis in chemical-induced F344 rat(hepatocellular carcinoma,HCC)model so as to explore the relationship of SERPINB5 with the occurrence and development of HCC.Methods We used 50 male F344 rats to induce HCC model.They were treated with diethylnirtosamine and N-nitrosomorpholine.Another 30 male F344 rats were used as controls.After 10 rats in model group and 6 in control group were sacrificed every 4 weeks,the pathological changes were evaluated by H&E staining.The expression of SERPINB5 was detected by immunohistochemistry.Results F344 rats liver cancer was confirmed16 and 20 weeks after HCC induction by diethylnirtosamine and N-nitrosomorpholine.Moreover,the morphological differences between HCC-induced and control groups were observed from week 4 induction.With the extension of chemical induction,the typical manifestations of hepatitis were shown at week12.Typical cirrhosis accompanied by micro-invasion of cancer cells was seen at week 16.At week 20,atypia of cancer cells was more obvious and the invasion of cancer cells was large.The expression of SERPINB5 was significantly decreased(P <0.05)compared with that at week 16 of cancer induction.Conclusion The expression of SERPINB5 is down-regulated in rat liver tissue,suggesting that SERPINB5 is closely related to the occurrence and development of liver carcinoma.Our findings provide new ideas for the early diagnosis and treatment of HCC.
引文
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[14]PRIETO V,LUDWIG JM,FARRIS AB,et al.Establishment of human metastatic colorectal cancer model in rabbit liver:A pilot study[J].PLoS One,2017,12(5):e0177212.
[15]GUO H,JING L,CHENG Y,et al.Down-regulation of the cyclin-dependent kinase inhibitor p57is mediated by Jab1/Csn5in hepatocarcinogenesis[J].Hepatology,2016,63(3):898-913.
[16]BERNARDO MM,DZINIC SH,MATTA MJ,et al.The opportunity of precision medicine for breast cancer with contextsensitive tumor suppressor maspin[J].J Cell Biochem,2017,118(7):1639-1647.
[17]GOULET B,KENNETTE W,ABLACK A,et al.Nuclear localization of maspin is essential for its inhibition of tumor growth and metastasis[J].Lab Invest,2011,91(8):1181-1187.
[18]GOULET B,CHAN G,CHAMBERS AF,et al.An emerging role for the nuclear localization of maspin in the suppression of tumor progression and metastasis[J].Biochem Cell Biol,2012,90(1):22-38.
[19]BANIAS L,GURZU S,KOVACS Z,et al.Nuclear maspin expression:A biomarker for budding assessment in colorectal cancer specimens[J].Pathol Res Pract,2017,213(9):1227-1230.
[20]ZHENG HC,Gong BC.The roles of maspin expression in gastric cancer:A meta-and bioinformatics analysis[J].Oncotarget,2017,8(39):66476-66490.
[21]孙海凤,郭亚焕,经里,等.SerpinB5和β-catenin在原发性肝细胞癌组织中的表达及作用[J].中国医师进修杂志,2017,40(5):385-389.
[2]SIEGEL RL,MILLER KD,JEMAL A.Cancer statistics,2017[J].CA Cancer J Clin,2017,67(1):7-30.
[3]DING XX,ZHU QG,ZHANG SM,et al.Precision medicine for hepatocellular carcinoma:Driver mutations and targeted therapy[J].Oncotarget,2017,8(33):55715-55730.
[4]张原青,郭津生.乙型肝炎病毒促进肝细胞性肝癌发生的机制[J].中华肝脏病杂志,2016,24(2):152-156.
[5]丛文铭.肝癌复发转移的分子机制与病理学评估策略[J].中华肝脏病杂志,2016,24(5):324-326.
[6]KIM M,JU H,LIM B,et al.Maspin genetically and functionally associates with gastric cancer by regulating cell cycle progression[J].Carcinogenesis,2012,33(12):2344-2350.
[7]MACHOWSKA M,WACHOWICZ K,SOPEL M,et al.Nuclear location of tumor suppressor protein maspin inhibits proliferation of breast cancer cells without affecting proliferation of normal epithelial cells[J].BMC Cancer,2014,28(18):142.
[8]LIU Z,SHI Y,MENG W,LIU Y,et al.Expression and localization of maspin in cervical cancer and its role in tumor progression and lymphangiogenesis[J].Arch Gynecol Obstet,2014,289(2):373-382.
[9]KIM JH,CHO NY,BAE JM,et al.Nuclear maspin expression correlates with the CpG island methylator phenotype and tumor aggressiveness in colorectal cancer[J].Int J Clin Exp Pathol,2015,8(2):1920-1928.
[10]LIN Z,LIU Y,SUN Y,et al.Expression of Ets-1,Ang-2 and maspin in ovarian cancer and their role in tumor angiogenesis[J].J Exp Clin Cancer Res,2011,25(30):31.
[11]陈海军,孙梓程,刘岩,等.化学诱导性大鼠肝癌形成过程中β-catenin表达的实验研究[J].中国癌症杂志,2015,25(4):300-304.
[12]刘蕊洁,杨先照,焦云涛,等.二乙基亚硝胺诱导肝细胞癌癌前病变动物模型研究[J].中西医结合肝病杂志,2015,25(3):162-164.
[13]杨新宇,徐蓓蕾,沈芸,等.诱发性大鼠肝癌模型的建立[J].哈尔滨商业大学学报(自然科学版).2015,31(4):401-409.
[14]PRIETO V,LUDWIG JM,FARRIS AB,et al.Establishment of human metastatic colorectal cancer model in rabbit liver:A pilot study[J].PLoS One,2017,12(5):e0177212.
[15]GUO H,JING L,CHENG Y,et al.Down-regulation of the cyclin-dependent kinase inhibitor p57is mediated by Jab1/Csn5in hepatocarcinogenesis[J].Hepatology,2016,63(3):898-913.
[16]BERNARDO MM,DZINIC SH,MATTA MJ,et al.The opportunity of precision medicine for breast cancer with contextsensitive tumor suppressor maspin[J].J Cell Biochem,2017,118(7):1639-1647.
[17]GOULET B,KENNETTE W,ABLACK A,et al.Nuclear localization of maspin is essential for its inhibition of tumor growth and metastasis[J].Lab Invest,2011,91(8):1181-1187.
[18]GOULET B,CHAN G,CHAMBERS AF,et al.An emerging role for the nuclear localization of maspin in the suppression of tumor progression and metastasis[J].Biochem Cell Biol,2012,90(1):22-38.
[19]BANIAS L,GURZU S,KOVACS Z,et al.Nuclear maspin expression:A biomarker for budding assessment in colorectal cancer specimens[J].Pathol Res Pract,2017,213(9):1227-1230.
[20]ZHENG HC,Gong BC.The roles of maspin expression in gastric cancer:A meta-and bioinformatics analysis[J].Oncotarget,2017,8(39):66476-66490.
[21]孙海凤,郭亚焕,经里,等.SerpinB5和β-catenin在原发性肝细胞癌组织中的表达及作用[J].中国医师进修杂志,2017,40(5):385-389.