RECK expression in pancreatic cancer: its correlation with lower invasiveness and better prognosis.
RECK expression in pancreatic cancer: its correlation with lower invasiveness and better prognosis.
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2003-05
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通讯作者：
T. Masui;R. Doi;T. Koshiba;K. Fujimoto;S. Tsuji;S. Nakajima;M. Koizumi;E. Toyoda;Sidhartha S. Tulachan;D. Ito;K. Kami;Tomohiko Mori;M. Wada;M. Noda;M. Imamura
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作者：
T. Masui;R. Doi;T. Koshiba;K. Fujimoto;S. Tsuji;S. Nakajima;M. Koizumi;E. Toyoda;Sidhartha S. Tulachan;D. Ito;K. Kami;Tomohiko Mori;M. Wada;M. Noda;M. Imamura
背景：具有Kazal基序的逆转诱导富含半胱氨酸蛋白(RECK)基因最初是作为转化抑制基因被分离出来的。RECK基因在正常器官中广泛表达，但在许多肿瘤细胞系中检测不到。当RECK在这些细胞系中人工表达时，至少负向调节基质金属蛋白酶(MMP9)-9、MMP2和MT1-MMP3的激活，并抑制这些细胞的侵袭和转移潜能。然而，这些观察结果的临床相关性还有待确定。本研究的目的是检测RECK在胰腺癌中的表达，并探讨其临床意义。我们还分析了RECK表达与基质金属蛋白酶活性的相关性。方法(A)用免疫组织化学方法检测50例胰腺浸润性导管癌组织中RECK的表达，并分析其与临床病理因素的关系，(B)应用明胶酶谱技术检测33例胰腺浸润性导管癌组织中潜伏型和激活型MMP2和MMP9的表达。用密度计量学方法定量明胶酶活性，并用活性的明胶酶带与活性的明胶酶带的总强度的比值作为明胶酶活性的指标。并对基质金属蛋白酶-9的活性进行了研究。结果50例导管癌组织中，RECK阳性表达26例(52%)。在正常胰腺组织中，腺泡细胞和β细胞均呈阳性反应，而导管细胞不呈阳性反应。RECK阳性肿瘤的侵袭性明显低于RECK阴性肿瘤(P=0.0438)。重要的是，RECK高表达的患者预后明显好于RECK阴性的患者(经LOG-RANK检验，P=0.0463)。凝胶成像分析显示RECK的表达水平与MMP2的活化程度呈显著负相关(P=0.0374)。结论RECK蛋白可能通过抑制MMP2的激活而影响胰腺癌的侵袭性，提示RECK蛋白作为胰腺癌预后分子标志物的潜在价值。
BACKGROUND The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene was initially isolated as a transformation suppressor gene. The RECK gene is expressed widely in normal organs but is undetectable in many tumor-derived cell lines. When artificially expressed in such cell lines, RECK negatively regulates at least matrix metalloprotease (MMP)-9, MMP-2, and MT1-MMP activation and suppresses the invasive and metastatic potentials of these cells. Clinical relevance of these observations, however, is yet to be established. The aim of this study was to examine RECK expression in pancreatic cancer, where intensive invasiveness and metastasis are frequently observed, and investigate its clinical significance. We also analyzed the correlation between RECK expression and MMP activation. METHODS (a) RECK expression in surgically resected tissue samples of invasive ductal carcinomas of the pancreas (n = 50) was examined immunohistochemically, and its correlation with clinicopathological factors was analyzed; and (b) gelatin zymography was used for the detection of latent and activated forms of MMP-2 and MMP-9 in some of the tissue samples (n = 33). The gelatinase activity was quantified by densitometory, and the ratio of intensity of the active MMP-2 band to the total intensity of the pro- and active MMP-2 bands was evaluated as an indicator of MMP-2 activation. The MMP-9 activation was also studied. RESULTS Among the 50 ductal carcinoma samples, 26 (52%) were stained positive for RECK. In the normal pancreas, both acinar and beta cells were stained positive, but ductal cells did not. Tumors with positive RECK staining were significantly less invasive as compared with RECK-negative tumors (P = 0.0438). Importantly, patients who had tumors with high RECK expression showed significantly better prognosis than those who had RECK-negative tumors (P = 0.0463, by Log-rank test). Zymographic analysis indicated significant inverse correlation between the level of RECK expression and extent of MMP-2 activation (P = 0.0374). CONCLUSIONS Our findings support the hypothesis that the RECK protein has negative effects on the invasiveness of pancreatic cancer by inhibiting MMP-2 activation and suggest the potential value of RECK as a prognostic molecular marker for pancreatic cancer.