Chang et al. Cancer Sci | February 2007 | vol. 98 | no. 2 | 173
© 2006 Japanese Cancer Association
mediators have been identiﬁed for ras-induced metastasis, including
and MMP. A genome-wide screening of ras targets
demonstrated that ras suppresses the expression of thrombospondin
1 and tissue inhibitor of metalloproteinase 1, two important
antimetastatic genes, to enhance cell invasion.
studies have also shown that inactivation of RASSF1A, a
tumor suppressor that exhibits antimetastatic activity, is closely
linked with ras mutation in cancer cells.
We now identify
RECK as a molecular target for the ras oncogene and show that
downregulation of RECK is associated with K-ras mutation
and lymph node metastasis in non-small cell lung tumor tissues
This study was supported by grants VGHNSU94-003 and VGHNSU
95-001 to Huang-Chou Chang and a grant from National Sun Yat-Sen
University–Kaohsiung Medical University Joint Research Center to
1 Noda M, Kitayama H, Matsuzaki T et al. Detection of genes with a potential
for suppressing the transformed phenotype associated with activated ras
genes. Proc Natl Acad Sci USA 1989; 86: 162– 6.
2 Takahashi C, Sheng Z, Horan TP et al. Regulation of matrix metalloproteinase-
9 and inhibition of tumor invasion by the membrane-anchored glycoprotein
RECK. Proc Natl Acad Sci USA 1998; 95: 13 221–6.
3 Oh J, Takahashi R, Kondo S et al. The membrane-anchored MMP inhibitor
RECK is a key regulator of extracellular matrix integrity and angiogenesis.
Cell 2001; 107: 789–800.
4 Masui T, Doi R, Koshiba T et al. RECK expression in pancreatic cancer:
its correlation with lower invasiveness and better prognosis. Clin Cancer
Res 2003; 9: 1779–84.
5 Span PN, Sweep CG, Manders P, Beex LV, Leppert D, Lindberg RL. Matrix
metalloproteinase inhibitor reversion-inducing cysteine-rich protein with
Kazal motifs: a prognostic marker for good clinical outcome in human breast
carcinoma. Cancer 2003; 97: 2710–15.
6 Takenaka K, Ishikawa S, Kawano Y et al. Expression of a novel matrix
metalloproteinase regulator, RECK, and its clinical signiﬁcance in resected
non-small cell lung cancer. Eur J Cancer 2004; 40: 1617–23.
7 Takeuchi T, Hisanaga M, Nagano M et al. The membrane-anchored matrix
metalloproteinase (MMP) regulator RECK in combination with MMP-9
serves as an informative prognostic indicator for colorectal cancer. Clin
Cancer Res 2004; 10: 5572 –9.
8 Bos JL. Ras oncogenes in human cancer: a review. Cancer Res 1989; 49:
9 Bondy GP, Wilson S, Chambers AF. Experimental metastatic ability of
H-ras-transformed NIH3T3 cells. Cancer Res 1985; 45: 6005– 9.
10 Muschel RJ, Williams JE, Lowy DR, Liotta LA. Harvey ras induction of
metastatic potential depends upon oncogene activation and the type of
recipient cell. Am J Pathol 1985; 121: 1–8.
11 Ichikawa T, Kiprianou N, Isaacs JT. Genetic instability and the acquisition
of metastatic ability by rat mammary cancer cells following v-H-ras
oncogene transfection. Cancer Res 1990; 50: 6349–57.
12 Chang HC, Cho CY, Hung WC. Silencing of the metastasis suppressor
RECK by RAS oncogene is mediated by DNA methyltransferase 3b-induced
promoter methylation. Cancer Res 2006; 66: 8413–20.
13 Liu LT, Chang HC, Chiang LC, Hung WC. Histone deacetylase inhibitor up-
regulates RECK to inhibit MMP-2 activation and cancer cell invasion.
Cancer Res 2003; 63: 3069 –72.
14 Echizenya M, Kondo S, Takahashi R et al. The membrane-anchored MMP-
regulator RECK is a target of myogenic regulatory factors. Oncogene 2005;
15 Takenaka K, Ishikawa S, Yanagihara K et al. Prognostic signiﬁcance of
reversion-inducing cysteine-rich protein with kazal motifs expression in
resected pathological stage IIIA N2 non-small cell lung cancer. Ann Surg
Oncol 2005; 12: 817–24.
16 Das PM, Singal R. DNA methylation and cancer. J Clin Oncol 2004; 22:
17 Sasahara RM, Takahashi C, Noda M. Involvement of the Sp1 site in ras-
mediated downregulation of the RECK metastasis suppressor gene. Biochem
Biophys Res Commun 1999; 264: 668 – 75.
18 Chang HC, Liu LT, Hung WC. Involvement of histone deacetylation in ras-
induced down-regulation of the metastasis suppressor RECK. Cell Signal
2004; 16: 675 – 9.
19 Mitsudomi T, Steinberg SM, Nau MM et al. p53 gene mutations in non-
small-cell lung cancer cell lines and their correlation with the presence of ras
mutations and clinical features. Oncogene 1992; 7: 171–80.
20 Falvella FS, Manenti G, Spinola M et al. Identiﬁcation of RASSF8 as a
candidate lung tumor suppressor gene. Oncogene 2006; 25: 3934– 8.
21 Shen H, Wang L, Spitz MR, Hong WK, Mao L, Wei Q. A novel
polymorphism in human cytosine DNA-methyltransferase-3B promoter is
associated with an increased risk of lung cancer. Cancer Res 2002; 62:
22 Lee SJ, Jeon HS, Jang JS et al. DNMT3B polymorphisms and risk of
primary lung cancer. Carcinogenesis 2005; 26: 403 – 9.
23 Vallbohmer D, Brabender J, Yang D et al. DNA methyltransferase messenger
RNA expression and aberrant methylation of CpG islands in non-small-cell
lung cancer: association and prognostic value. Clin Lung Cancer 2006; 8:
24 Wang J, Walsh G, Liu DD, Lee JJ, Mao L. Expression of ∆DNMT3B
variants and its association with promoter methylation of p16 and RASSF1A
in primary non-small cell lung cancer. Cancer Res 2006; 66: 8361–6.
25 Hall A. Ras-related GTPases and cytoskeleton. Mol Biol Cell 1992; 3:
26 Zhang Z, Vuori K, Wang H, Reed JC, Ruoslahti E. Integrin activation by R-ras.
Cell 1996; 85: 61–9.
27 Schmidt CR, Gi YJ, Coffey RJ, Beauchamp RD, Pearson AS. Oncogenic
Ras dominates overexpression of E-cadherin in malignant transformation of
intestinal epithelial cells. Surgery 2004; 136: 303 –9.
28 Rak J, Mitsuhashi Y, Bayko L et al. Mutant ras oncogenes upregulate
VEGF/VPF expression: implications for induction and inhibition of tumor
angiogenesis. Cancer Res 1995; 55: 4575–80.
29 Pironin M, Clement G, Benzakour O, Lawrence D, Vigier P. Growth in
serum-free medium of NIH3T3 cells transformed by the EJ-H-ras oncogene:
evidence for multiple autocrine growth factors. Int J Cancer 1992; 51:
30 Zuber J, Tchernitsa OI, Hinzmann B et al. A genome-wide survey of RAS
transformation targets. Nat Genet 2002; 24: 144– 52.
31 Dammann R, Schagdarsurengin U, Liu L et al. Frequent RASSF1A
promoter hypermethylation and K-ras mutations in pancreatic carcinoma.
Oncogene 2003; 22: 3806–12.
32 Kim DH, Kim JS, Park JH et al. Relationship of Ras association domain
family 1 methylation and K-ras mutation in primary non-small cell lung
cancer. Cancer Res 2003; 63: 6206–11.