肝细胞癌患者血浆基质金属蛋白酶的检测及临床意义
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摘要
目的探讨基质金属蛋白酶(MMPs)在肝细胞癌(HCC)患者中的表达水平及其与临床病理学特征的关系。方法选取2015年10月-2018年5月在首都医科大学附属北京佑安医院住院治疗的患者131例,其中乙型肝炎肝硬化患者35例,HCC患者96例;另选取同期门诊体检的健康对照者20例;采用悬浮液相芯片技术检测患者治疗前血浆MMP-1、MMP-2、MMP-7、MMP-9、MMP-10水平。非正态分布的计量资料2组间比较采用Mann-Whitney U检验,3组间比较采用Kruskal-Wallis H检验,进一步两两比较采用Dunn-Bonferroni检验,2组样本的相关性检验采用Spearman相关分析。结果 HCC患者血浆MMP-1水平为8134. 84(6147. 94～11 148. 47) pg/ml、MMP-7水平为6541. 58(3906. 63～9033. 12) pg/ml,均高于肝炎肝硬化组及健康对照组,差异均有统计学意义(χ~2值分别为23. 521、66. 112,P值均<0. 001); HCC患者血浆MMP-2水平为103 774. 45(90 485. 91～123 673. 90)pg/ml,高于健康对照组,差异有统计学意义(P <0. 05)。肿瘤直径≥5 cm、伴有远处转移、合并门静脉侵犯、临床分期Ⅲ/Ⅳ期或病理ESⅢ/Ⅳ级组患者血浆MMP-1水平分别高于肿瘤直径<5 cm(Z=-7. 313,P <0. 001)、无远处转移(Z=-6. 569,P <0. 001)、无门静脉侵犯(Z=-6. 051,P <0. 001)、临床分期Ⅰ/Ⅱ期(Z=-5. 844,P <0. 001)、病理ESⅠ/Ⅱ级组(Z=-7. 423,P <0. 001)患者,差异均有统计学意义。伴有远处转移、合并门静脉侵犯、临床分期Ⅲ/Ⅳ期、病理ESⅢ/Ⅳ级组患者血浆MMP-7水平分别高于无远处转移(Z=-3. 454,P=0. 001)、无门静脉侵犯(Z=-3. 846,P <0. 001)、临床分期Ⅰ/Ⅱ期(Z=-2. 285,P=0. 022)、病理ESⅠ/Ⅱ级组(Z=-3. 287,P=0. 001)患者,差异均有统计学意义。结论 HCC患者MMP-1和MMP-7的表达与HCC转移、门静脉侵犯、临床分期及病理学分级相关,可协助判断HCC患者的肿瘤侵袭严重程度及预后。
Objective To investigate the expression of matrix metalloproteinases( MMPs) in patients with hepatocellular carcinoma( HCC)and its association with clinicopathological features. Methods A total of 131 patients who were hospitalized and treated in Beijing YouAn hospital from October 2015 to May 2018 were enrolled,and among these patients,35 had hepatitis B cirrhosis and 96 had HCC. A total of20 healthy controls who underwent physical examination at the outpatient service during the same period of time were enrolled as healthy control group. Suspension phase chip technology was used to measure the plasma levels of MMP-1,MMP-2,MMP-7,MMP-9,and MMP-10 before treatment. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups,and the Kruskal-Wallis H test was used for comparison between three groups; the Spearman correlation analysis was performed to investigate correlation. Results The HCC group had a plasma level of MMP-1 of 8134. 84( 6147. 94-11 148. 47) pg/ml and a plasma level of MMP-7 of 6541. 58( 3906. 63-9033. 12) pg/ml,which were significantly higher than the plasma levels of MMP-1 and MMP-7 in the hepatitis B cirrhosis group and the healthy control group( χ~2= 23. 521 and 66. 112,both P < 0. 001). The HCC group had a plasma level of MMP-2 of 103 774. 45( 90 485. 91-123 673. 90) pg/ml,which was significantly higher than that in the healthy control group( P< 0. 05). The patients with a tumor diameter of ≥5 cm,distant metastasis,portal venous invasion,clinical stage Ⅲ/Ⅳ,or Edmondson-Steiner( ES) grade Ⅲ/Ⅳ had a significantly higher plasma level of MMP-1 than those with a tumor diameter of < 5 cm( Z =-7. 313,P< 0. 001),without distant metastasis( Z =-6. 569,P < 0. 001),without portal venous invasion( Z =-6. 051,P < 0. 001),with clinical stage Ⅰ/Ⅱ( Z =-5. 844,P < 0. 001),or with ES grade Ⅰ/Ⅱ( Z =-7. 423,P < 0. 001). The patients with distant metastasis,portal venous invasion,clinical stage Ⅲ/Ⅳ,or ES grade Ⅲ/Ⅳ had a significantly higher plasma level of MMP-7 than those without distant metastasis( Z =-3. 454,P = 0. 001),without portal venous invasion( Z =-3. 846,P < 0. 001),with clinical stage Ⅰ/Ⅱ( Z =-2. 285,P= 0. 022),or with ES grade Ⅰ/Ⅱ( Z =-3. 287,P = 0. 001). Conclusion The expression of MMP-1 and MMP-7 in HCC patients is associated with HCC metastasis,portal venous invasion,clinical stage,and pathological grade and can help to evaluate the severity and prognosis of tumor invasion in HCC patients.
Objective To investigate the expression of matrix metalloproteinases( MMPs) in patients with hepatocellular carcinoma( HCC)and its association with clinicopathological features. Methods A total of 131 patients who were hospitalized and treated in Beijing YouAn hospital from October 2015 to May 2018 were enrolled,and among these patients,35 had hepatitis B cirrhosis and 96 had HCC. A total of20 healthy controls who underwent physical examination at the outpatient service during the same period of time were enrolled as healthy control group. Suspension phase chip technology was used to measure the plasma levels of MMP-1,MMP-2,MMP-7,MMP-9,and MMP-10 before treatment. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups,and the Kruskal-Wallis H test was used for comparison between three groups; the Spearman correlation analysis was performed to investigate correlation. Results The HCC group had a plasma level of MMP-1 of 8134. 84( 6147. 94-11 148. 47) pg/ml and a plasma level of MMP-7 of 6541. 58( 3906. 63-9033. 12) pg/ml,which were significantly higher than the plasma levels of MMP-1 and MMP-7 in the hepatitis B cirrhosis group and the healthy control group( χ~2= 23. 521 and 66. 112,both P < 0. 001). The HCC group had a plasma level of MMP-2 of 103 774. 45( 90 485. 91-123 673. 90) pg/ml,which was significantly higher than that in the healthy control group( P< 0. 05). The patients with a tumor diameter of ≥5 cm,distant metastasis,portal venous invasion,clinical stage Ⅲ/Ⅳ,or Edmondson-Steiner( ES) grade Ⅲ/Ⅳ had a significantly higher plasma level of MMP-1 than those with a tumor diameter of < 5 cm( Z =-7. 313,P< 0. 001),without distant metastasis( Z =-6. 569,P < 0. 001),without portal venous invasion( Z =-6. 051,P < 0. 001),with clinical stage Ⅰ/Ⅱ( Z =-5. 844,P < 0. 001),or with ES grade Ⅰ/Ⅱ( Z =-7. 423,P < 0. 001). The patients with distant metastasis,portal venous invasion,clinical stage Ⅲ/Ⅳ,or ES grade Ⅲ/Ⅳ had a significantly higher plasma level of MMP-7 than those without distant metastasis( Z =-3. 454,P = 0. 001),without portal venous invasion( Z =-3. 846,P < 0. 001),with clinical stage Ⅰ/Ⅱ( Z =-2. 285,P= 0. 022),or with ES grade Ⅰ/Ⅱ( Z =-3. 287,P = 0. 001). Conclusion The expression of MMP-1 and MMP-7 in HCC patients is associated with HCC metastasis,portal venous invasion,clinical stage,and pathological grade and can help to evaluate the severity and prognosis of tumor invasion in HCC patients.
引文
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[9]SAKAMOTO Y,MAFUNE K,MORI M,et al. Overexpression of MMP-9 correlates with growth of small hepatocellular carcinoma[J]. Int J Oncol,2000,17(2):237-243.
[10]LIAO M,TONG P,ZHAO J,et al. Prognostic value of matrix metalloproteinase-1/proteinase-activated receptor-1 signaling axis in hepatocellular carcinoma[J]. Pathol Oncol Res,2012,18(2):397-403.
[11]ALTADILL A,RODRGUEZ M,GONZLEZ LO,et al. Liver expression of matrix metalloproteases and their inhibitors in hepatocellular carcinoma[J]. Dig Liver Dis,2009,41(10):740-748.
[12]YANG L,RONG W,XIAO T,et al. Secretory/releasing proteome-based identification of plasma biomarkers in HBV-associated hepatocellular carcinoma[J]. Sci China Life Sci,2013,56(7):638-646.
[13]CHEN GL,SHEN TC,CHANG WS,et al. The contribution of MMP-7 promoter polymorphisms to Taiwan lung cancer susceptibility[J]. Anticancer Res,2018,38(10):5671-5677.
[14]VENTO SI,JOUHI L,MOHAMED H,et al. MMP-7 expression may influence the rate of distant recurrences and disease-specific survival in HPV-positive oropharyngeal squamous cell carcinoma[J]. Virchows Arch,2018,472(6):975-981.
[15]WANG J,SU H,HAN X,et al. Inhibition of fibroblast growth factor receptor signaling impairs metastasis of hepatocellular carcinoma[J]. Tumour Biol,2014,35(11):11005-11011.
[16]ISHII Y,NAKASATO Y,KOBAYASHI S,et al. A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma[J]. J Exp Clin Cancer Res,2003,22(3):461-470.
[17]RONG W,ZHANG Y,YANG L,et al. Post-surgical resection prognostic value of combined OPN,MMP7,and PSG9 plasma biomarkers in hepatocellular carcinoma[J]. Front Med,2018.[Epub ahead of print]
[18]KANG KF,ZHANG X,CHEN XW,et al. Expression and significance of MMP-7 and PTEN protein in primary human hepatocellular carcinoma[J]. Cancer Res Prevent Treat,2010,37(6):652-655.(in Chinese)康凯夫,张鑫,陈小伍,等. MMP-和PTEN蛋白在原发性肝细胞性肝癌中的表达及其意义[J].肿瘤防治研究,2010,37(6):652-655.
[19]XIANG ZL,ZENG ZC,TANG ZY,et al. Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma[J]. Mol Biol Rep,2011,38(5):3531-3539.
[20]NART D,YAMAN B,YILMAZ F,et al. Expression of matrix metalloproteinase-9 in predicting prognosis of hepatocellular carcinoma after liver transplantation[J]. Liver Transpl,2010,16(5):621-630.
[21]KWON OS,LIM DY,KWON KA,et al. Clinical usefulness of plasma activities of gelatinase(matrix metalloproteinase-2and 9)in chronic liver disease[J]. Taehan Kan Hakhoe Chi,2003,9(3):222-230.
[22]KUYVENHOVEN JP,van HOEK B,BLOM E,et al. Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma[J]. Thromb Haemost,2003,89(4):718-725.
[23]GAO ZH,TRETIAKOVA MS,LIU WH,et al. Association of E-cadherin,matrix metalloproteinases,and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma[J]. Mod Pathol,2006,19(4):533-540.
[24]BODEY B,BODEY B Jr,SIEGEL SE,et al. Immunocytochemical detection of MMP-3 and-10 expression in hepatocellular carcinomas[J]. Anticancer Res,2000,20(6B):4585-4590.
[25]GARCíA-IRIGOYEN O,LATASA MU,CAROTTI S,et al. Matrix metalloproteinase 10 contributes to hepatocarcinogenesis in a novel crosstalk with the stromal derived factor 1/C-X-C chemokine receptor 4 axis[J]. Hepatology,2015,62(1):166-178.
[2]SáNCHEZ-LORENCIO MI,SAENZ L,RAMIREZ P,et al. Matrix metalloproteinase 1 as a novel biomarker for monitoring hepatocellular carcinoma in liver transplant patients[J]. Transplant Proc,2018,50(2):623-627.
[3]YAO Q,KOU L,TU Y,et al. MMP-responsive'smart'drug delivery and tumor targeting[J]. Trends Pharmacol Sci,2018,39(8):766-781.
[4]MARCHENKO GN,STRONGIN AY. MMP-28,a new human matrix metalloproteinase with an unusual cysteine-switch sequence is widely expressed in tumors[J]. Gene,2001,265(1-2):87-93.
[5]National Health and Family Planning Commission of the People's Republic of China. Diagnosis,management,and treatment of hepatocellular carcinoma(V2017)[J]. J Clin Hepatol,2017,33(8):1419-1431.(in Chinese)中华人民共和国国家卫生和计划生育委员会.原发性肝癌诊疗规范(2017年版)[J].临床肝胆病杂志,2017,33(8):1419-1431.
[6]Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association. The guideline of prevention and treatment for chronic hepatitis B:A 2015 update[J]. J Clin Hepatol,2015,31(12):1941-1960.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[7]WINER A,ADAMS S,MIGNATTI P. Matrix metalloproteinase inhibitors in cancer therapy:Turning past failures into future successes[J]. Mol Cancer Ther,2018,17(6):1147-1155.
[8]KIM JH,KIM TH,JANG JW,et al. Analysis of matrix metalloproteinase mRNAs expressed in hepatocellular carcinoma cell lines[J]. Mol Cells,2001,12(1):32-40.
[9]SAKAMOTO Y,MAFUNE K,MORI M,et al. Overexpression of MMP-9 correlates with growth of small hepatocellular carcinoma[J]. Int J Oncol,2000,17(2):237-243.
[10]LIAO M,TONG P,ZHAO J,et al. Prognostic value of matrix metalloproteinase-1/proteinase-activated receptor-1 signaling axis in hepatocellular carcinoma[J]. Pathol Oncol Res,2012,18(2):397-403.
[11]ALTADILL A,RODRGUEZ M,GONZLEZ LO,et al. Liver expression of matrix metalloproteases and their inhibitors in hepatocellular carcinoma[J]. Dig Liver Dis,2009,41(10):740-748.
[12]YANG L,RONG W,XIAO T,et al. Secretory/releasing proteome-based identification of plasma biomarkers in HBV-associated hepatocellular carcinoma[J]. Sci China Life Sci,2013,56(7):638-646.
[13]CHEN GL,SHEN TC,CHANG WS,et al. The contribution of MMP-7 promoter polymorphisms to Taiwan lung cancer susceptibility[J]. Anticancer Res,2018,38(10):5671-5677.
[14]VENTO SI,JOUHI L,MOHAMED H,et al. MMP-7 expression may influence the rate of distant recurrences and disease-specific survival in HPV-positive oropharyngeal squamous cell carcinoma[J]. Virchows Arch,2018,472(6):975-981.
[15]WANG J,SU H,HAN X,et al. Inhibition of fibroblast growth factor receptor signaling impairs metastasis of hepatocellular carcinoma[J]. Tumour Biol,2014,35(11):11005-11011.
[16]ISHII Y,NAKASATO Y,KOBAYASHI S,et al. A study on angiogenesis-related matrix metalloproteinase networks in primary hepatocellular carcinoma[J]. J Exp Clin Cancer Res,2003,22(3):461-470.
[17]RONG W,ZHANG Y,YANG L,et al. Post-surgical resection prognostic value of combined OPN,MMP7,and PSG9 plasma biomarkers in hepatocellular carcinoma[J]. Front Med,2018.[Epub ahead of print]
[18]KANG KF,ZHANG X,CHEN XW,et al. Expression and significance of MMP-7 and PTEN protein in primary human hepatocellular carcinoma[J]. Cancer Res Prevent Treat,2010,37(6):652-655.(in Chinese)康凯夫,张鑫,陈小伍,等. MMP-和PTEN蛋白在原发性肝细胞性肝癌中的表达及其意义[J].肿瘤防治研究,2010,37(6):652-655.
[19]XIANG ZL,ZENG ZC,TANG ZY,et al. Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma[J]. Mol Biol Rep,2011,38(5):3531-3539.
[20]NART D,YAMAN B,YILMAZ F,et al. Expression of matrix metalloproteinase-9 in predicting prognosis of hepatocellular carcinoma after liver transplantation[J]. Liver Transpl,2010,16(5):621-630.
[21]KWON OS,LIM DY,KWON KA,et al. Clinical usefulness of plasma activities of gelatinase(matrix metalloproteinase-2and 9)in chronic liver disease[J]. Taehan Kan Hakhoe Chi,2003,9(3):222-230.
[22]KUYVENHOVEN JP,van HOEK B,BLOM E,et al. Assessment of the clinical significance of serum matrix metalloproteinases MMP-2 and MMP-9 in patients with various chronic liver diseases and hepatocellular carcinoma[J]. Thromb Haemost,2003,89(4):718-725.
[23]GAO ZH,TRETIAKOVA MS,LIU WH,et al. Association of E-cadherin,matrix metalloproteinases,and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma[J]. Mod Pathol,2006,19(4):533-540.
[24]BODEY B,BODEY B Jr,SIEGEL SE,et al. Immunocytochemical detection of MMP-3 and-10 expression in hepatocellular carcinomas[J]. Anticancer Res,2000,20(6B):4585-4590.
[25]GARCíA-IRIGOYEN O,LATASA MU,CAROTTI S,et al. Matrix metalloproteinase 10 contributes to hepatocarcinogenesis in a novel crosstalk with the stromal derived factor 1/C-X-C chemokine receptor 4 axis[J]. Hepatology,2015,62(1):166-178.