RECK expression in pancreatic cancer: Its correlation with lower invasiveness and better prognosis

Toshihiko Masui, Ryuichiro Doi, Takatomo Koshiba, Koji Fujimoto, Shoichiro Tsuji, Sanae Nakajima, Masayuki Koizumi, Eiji Toyoda, Sidhartha Tulachan, Daisuke Ito, Kazuhiro Kami, Tomohiko Mori, Michihiko Wada, Makoto Noda, Masayuki Imamura

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Abstract

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 β 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.

Original languageEnglish
Pages (from-to)1779-1784
Number of pages6
JournalClinical Cancer Research
Volume9
Issue number5
Publication statusPublished - 01-05-2003

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Metalloproteases
Pancreatic Neoplasms
Neoplasms
Pancreatic Ductal Carcinoma
Suppressor Genes
Gelatinases
Ductal Carcinoma
Acinar Cells
Gelatin
Tumor Cell Line
Genes
Cysteine
Pancreas
Proteins
Staining and Labeling
Neoplasm Metastasis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Masui, T., Doi, R., Koshiba, T., Fujimoto, K., Tsuji, S., Nakajima, S., ... Imamura, M. (2003). RECK expression in pancreatic cancer: Its correlation with lower invasiveness and better prognosis. Clinical Cancer Research, 9(5), 1779-1784.
Masui, Toshihiko ; Doi, Ryuichiro ; Koshiba, Takatomo ; Fujimoto, Koji ; Tsuji, Shoichiro ; Nakajima, Sanae ; Koizumi, Masayuki ; Toyoda, Eiji ; Tulachan, Sidhartha ; Ito, Daisuke ; Kami, Kazuhiro ; Mori, Tomohiko ; Wada, Michihiko ; Noda, Makoto ; Imamura, Masayuki. / RECK expression in pancreatic cancer : Its correlation with lower invasiveness and better prognosis. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 5. pp. 1779-1784.
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title = "RECK expression in pancreatic cancer: Its correlation with lower invasiveness and better prognosis",
abstract = "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 β 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.",
author = "Toshihiko Masui and Ryuichiro Doi and Takatomo Koshiba and Koji Fujimoto and Shoichiro Tsuji and Sanae Nakajima and Masayuki Koizumi and Eiji Toyoda and Sidhartha Tulachan and Daisuke Ito and Kazuhiro Kami and Tomohiko Mori and Michihiko Wada and Makoto Noda and Masayuki Imamura",
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Masui, T, Doi, R, Koshiba, T, Fujimoto, K, Tsuji, S, Nakajima, S, Koizumi, M, Toyoda, E, Tulachan, S, Ito, D, Kami, K, Mori, T, Wada, M, Noda, M & Imamura, M 2003, 'RECK expression in pancreatic cancer: Its correlation with lower invasiveness and better prognosis', Clinical Cancer Research, vol. 9, no. 5, pp. 1779-1784.

RECK expression in pancreatic cancer : Its correlation with lower invasiveness and better prognosis. / Masui, Toshihiko; Doi, Ryuichiro; Koshiba, Takatomo; Fujimoto, Koji; Tsuji, Shoichiro; Nakajima, Sanae; Koizumi, Masayuki; Toyoda, Eiji; Tulachan, Sidhartha; Ito, Daisuke; Kami, Kazuhiro; Mori, Tomohiko; Wada, Michihiko; Noda, Makoto; Imamura, Masayuki.

In: Clinical Cancer Research, Vol. 9, No. 5, 01.05.2003, p. 1779-1784.

Research output: Contribution to journalArticle

TY - JOUR

T1 - RECK expression in pancreatic cancer

T2 - Its correlation with lower invasiveness and better prognosis

AU - Masui, Toshihiko

AU - Doi, Ryuichiro

AU - Koshiba, Takatomo

AU - Fujimoto, Koji

AU - Tsuji, Shoichiro

AU - Nakajima, Sanae

AU - Koizumi, Masayuki

AU - Toyoda, Eiji

AU - Tulachan, Sidhartha

AU - Ito, Daisuke

AU - Kami, Kazuhiro

AU - Mori, Tomohiko

AU - Wada, Michihiko

AU - Noda, Makoto

AU - Imamura, Masayuki

PY - 2003/5/1

Y1 - 2003/5/1

N2 - 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 β 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.

AB - 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 β 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.

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