[ ] : MMP22,MMP29 TIMP21, TIMP22

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1 212 BULL HUNAN MED UNIV 2003,28 (3) MMP22,MMP29,TIMP21 TIMP22,,, (, ) [ ] : MMP22,MMP29 TIMP21, TIMP22 mrna : 56 MMP22 mrna, TIMP22 mrna ; MMP22,MMP29, TIMP21, TIMP22 : MMP22 mrna, TIMP22 mrna,mmp22,mmp29,timp21 TIMP22 48 (85. 7 %),35 (62. 5 %),44 (78. 6 %),41 (73. 2 %),30 (53. 6 %),38 (68 %) MMP22 mrna,mmp22,mmp29, TIMP21 ( P < 0. 01, P < 0. 05) TIMP22 mrna TIMP22 ; MMP22 mrna MMP22 ( r = , P < ; r = , P < 0. 05) MMP22 mrna ( r = , P < ; r = , P < 0. 05) ; MMP29 ( P < 0. 05) Kaplan2Meier MMP22, MMP29 ( P < 0. 01, P < 0. 05) Cox MMP22,MMP29 : MMP22,MMP29 TIMP22, MMP22 ;MMP22,MMP29 [ ] ; ; ; ; [ ] R [ ] A [ ] (2003) Expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in the hepatocellular carcinomas WEI Qi2you,WU Yuan2qing, FAN Song2qing, et al. ( Deptartment of Pathology, Second Xiangya Hospital, Central South University, Changsha , China) Abstract :Objective To explore the expression and clinical prognostic significance of matrix metallopro2 teinase22 mrna (MMP22 mrna),tissue inhibitor of matrix metalloproteinase22 mrna ( TIMP22 mrna), matrix metalloproteinase22 protein (MMP22),matrix metalloproteinase29 protein (MMP29),tissue inhibitor of matrix metalloproteinase21 protein ( TIMP21),and tissue inhibitor of matrix metalloproteinase22 protein ( TIMP2 2) in the hepatocellular carcinomas (HCCs). Methods Fifty2six specimens of HCCs from 56 patients, who were followed2up, were investigated by in situ hybridization with specific probes for MMP22,TIMP22, and by immunohistochemistry with anti2mmp22, MMP29 and anti2timp21, TIMP22 monoclonal antibody. We analyzed the data with chi2square test, spearman s correlation analysis, monovariate Kaplan2Meier plot and multivariate Cox regression analysis. Results The positive expression of MMP22mRNA, TIMP22mRNA, MMP22 pro2 tein, MMP29 protein, TIMP21 protein and TIMP22 protein in the 56 HCCs cases were 48 (85. 7 %), 35 (62. 5 %), 44 (78. 6 %), 41 (73. 2 %), 30 (53. 6 %),and 38 (68 %), respectively. We found over2expression of MMP22 mrna, MMP22 protein, and MMP29 protein,but low expression of TIMP21 protein in the 56 cases : : (19502),,,,

2 MMP22,MMP29,TIMP21 TIMP22, 213 of HCCs ( P < 0. 01, P < 0. 05). There was a positive association between TIMP22mRNA and TIMP22 pro2 tein expression,and between MMP22 mrna and MMP22 protein in HCCs, respectively ( r = , P < ; r = , P < 0. 05). Over2expression of MMP22 mrna was positively correlated to the tumor size and TNM classification ( r = , P < ; r = , P < 0. 05), and MMP29 protein was related to shortened survival ( P < 0. 05). In both monovariate Kaplan2Meir plot and multivariate Cox regression anal2 ysis, the expression of MMP22 protein and MMP29 protein were linked to unfavorable prognosis. These results were further confirmed by multivariate analysis in which MMP22 protein and MMP29 protein emerged as inde2 pendent prognostic factors for poor survival regardless of the age, tumor size, tumor grades, TNM classification and expression of MMP22mRNA,TIMP22mRNA,TIMP21 protein and TIMP22 protein. The hazard ratios of ex2 pression of MMP22 protein and MMP29 protein were and , respectively. Conclusion The over2 expression of MMP22mRNA,MMP22 protein and MMP29 protein and the imbalance between MMP22 and TIMP2 2 play pivotal roles in the degradation of excellular matrix of HCCs. MMP22 and MMP29 immunoreactive protein have been closely related to a shortened survival independent of major prognostic indicators in the primary HCC and increase the risk of the patients after the operation. Key words : carcinoma ; hepatocellular carcinoma ; matrix metalloproteinase ; tissue inhibitor of matrix metalloproteinases ; prognosis [Bull Hunan Med Univ,2003,28 (3) : ], (MMPs), ( MMP22 MMP29),MMP22 ;MMP29 TIMP22,TIMP21, [1 ] MMPs,TIMPs [2 4 ] MMP22,MMP29 TIMP21,TIMP22 mrna, MMP22,MMP29, TIMP21, TIMP (1) : ; 38, 18, ( ) ; UICC : 14, 22, 12, 8 Edmondson, 7, 28, 21 (2) : TIMP22,MMP22, TIMP22 : 5 2GAA GCA GCG TCG CCA GCA GCA GGA GGC CGA23 ; 5 2 GTA GAT AAA CTC TAT ATC CTT CTC AGG CCC23 ; 5 2TGG GTC CTC GAT GTC GAG AAA CTC CTG CTT23 MMP22 : 5 2GTT GCA GCCTC CTT GGG GCA GCC ATA GAA23 ; 5 2 GGA AGC GGA ATG GAA ACT TGC AGG GCT GTC23 ; 5 2CCA AAC TTC ACG CTC TTC AG A CTT TGG TTC23, TIMP21,TIMP22,MMP22,MMP %,, 4 m,, h,, 1 DEPC PBS TIMP22,MMP22,,,,AEC SP (UltraSensitive TMS P kit), TIMP21,PBS

3 214,2003,28 (3),AEC , TIMP22 mrna, MMP22 mrna, TIMP21, TIMP22, MMP22, MMP29 : 0, 1, 2 ; < 5 % 0, 5 % 25 % 1,26 % 50 % 2, > 50 % 3 0 ( - ),1 ( + ) [7 ] 1. 3 SPSS , Spearman s ; Kaplan2Meier Cox MMPs TIMPs 56 MMP22 mrna 48 ( %), TIMP22 mrna 35 (62. 5 %) ; MMP22,MMP29, TIMP21,TIMP22 44 (78. 6 %), 41 ( %), 30 ( %), 38 (68 %) ; ( 1,2) MMP22 mrna,mmp22,mmp29,timp22 ( P < 0. 01, P ) TIMP22 mrna TIMP22 ; MMP22 mrna MMP22 ( r = , P < ; r = , P < 0. 05) 1 MMP22 mrna ( ISH 400 AEC ) Fig. 1 MMP22 mrna expression in cytoplasm of the HCC ( ISH 400 AEC staining) 2 MMP22 ( ICH 400 AEC ) Fig. 2 MMP22 protein expression in cytoplasm of the HCC( ISH 400 AEC staining) 2. 2 MPs TIMPs MMP22 mrna, ( r = , P ; r = , P 0. 05) MMP29 ( r = , P 0. 05) TIMP22 mrna, TIMP21, TIMP MMPs TIMPs 56,, 6 62, 20. 3, 31 Kaplan2Meier % MMP22, MMP29 ( 3, 4) Cox, MMP22, MMP29 ( ) MMP22,MMP29 exp ( ) , ( P 0. 01, P 0. 05) Cox 2 P MMP MMP

4 MMP22,MMP29,TIMP21 TIMP22, MMP22 Kaplan2Meier Fig. 3 Kaplan2Meier curves of the expression of MMP22 protein in HCC 4 MMP29 Kaplan2Meier Fig. 4 Kaplan2Meier curves of the expression of MMP29 protein in HCC, 3, mrna,, MMP29 mrna ; MMP22 [1 ] mrna A (MMP22) B (MMP29), MMP29,,, MMP29 MMP22 TIMP22 [2 ] MMP22 mrna, MMP29 TIMP21 ; TIMP22,, TIMP21 MMP22,MMP29,, MMP22 1 :1, MMP22,MMP29 mrna,,mmp22 TIMP22,,MMP2 MMP22 ( 2, 80 %,95 %), TIMP22,,,, [4 7 ], 90, ( ) ;,,,,, (MMPs) MMP22 mrna TIMP21,TIMP22 TIMP22 mrna,mmp22, TIMP22 MMP22 MMP29,,TIMP22 MMP22,MMP29, [2 4 ], 1 :1 Arii 23, TIMP21,TIMP22,, MMP22,MMP29 MMP22,MMP29, ( TIMP22, TIMP21),

5 216,2003,28 (3), MMP22,MMP29,, [4,5,8 ] MMP22, MMP29 TIMP22, TIMP21 mrna ;,, Kaplan2Meier Cox MMP2 2,MMP29 MMP22,MMP29 MMP TIMP22 mrna,mmp22mrna,timp21,timp22,,,,, MMP22,MMP29,, : MMP22,MMP29 MMP22,MMP29 TIMP21,TIMP22,,,MMP22, MMP29 : [ 1 ] Anne TM, Paakko P, Sequeiros GB, et al. Matrix metalloproteinase2 2 immunoreactive protein :A marker of aggressiveness in breast carci2 noma[j ]. Cancer, 1998, 83 : [2 ] Arii S, Mise M, Harada T, et al. Overexpression of matrix metallo2 proteinase 9 gene in hepatocellular carcinoma with invasive potential [J ]. Hepatology, 1996, 24 : [3 ] Musso O, Theret N, Campion JP, et al. In situ detection of matrix metalloproteinase22 ( MMP22 ) and the metalloproteinase inhibitor TIMP22 transcript in human primary hepatocellular carcinoma and in liver metastasis[j ]. J Hepatol, 1997, 26 : [4 ] Giannelli G, Bergamini C, Marinosci F, et al. Clinical role of MMP2 2/ TIMP22 imbalance in hepatocellular carcinoma [J ]. Int J Cancer, 2002, 97 : [5 ],,. [J ].,2002,21 (3) : [6 ] Heppner KJ, Matrisisan LM, Jensen RA, et al. Expression of most matrix metalloproteinase family member in breast cancers represents a tumor 2induced host response [J ]. Am J Pathol, 1996, 149 : [7 ] Yoshikawa T, Saitoh M, Tsuburaya A, et al. Tissue inhibitor of ma2 trix metalloproteinase21 in the plasma of patients with gastric carcino2 ma : a possible marker for serosal invasion and metastasis[j ]. Can2 cer, 1999, 86 : [8 ],,. 22 [J ].,2002,21 (1) : ( )

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