RECK expression in pancreatic cancer: its correlation with lower invasiveness and better prognosis.
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.
Masui
Toshihiko
T
Department of Surgery, Kyoto University Graduate School of Medicine, Sakyo, Japan. masui@kuhp.kyoto-u.ac.jp
Doi
Ryuichiro
R
Koshiba
Takatomo
T
Fujimoto
Koji
K
Tsuji
Shoichiro
S
Nakajima
Sanae
S
Koizumi
Masayuki
M
Toyoda
Eiji
E
Tulachan
Sidhartha
S
Ito
Daisuke
D
Kami
Kazuhiro
K
Mori
Tomohiko
T
Wada
Michihiko
M
Noda
Makoto
M
Imamura
Masayuki
M
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate
D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C115460:RECK protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9