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Genome Science Division [Y. H., M. I., H. T., S. T., H. A.], Division of Molecular Biology and Medicine [T. K.], Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan, and First Department of Surgery, Osaka City University Medical School, Osaka 545-8586, Japan [M. Y., K. H.]
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-1-antitrypsin, and galectin 4
and down-regulation of cytidine deaminase in cells prone to peritoneal
dissemination. Genes highly correlated with invasion or peritoneal
dissemination of gastric cancer, such as E-cadherin or integrin
ß4, were down-regulated in both of the derivative cell
lines analyzed in this study. This is the first demonstration of global
gene expression analysis of gastric cancer cells with different
metastatic potentials, and these results provide a new insight in the
study of human gastric cancer metastasis. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Although aspects of gastric cancer metastasis remain to be
elucidated, adhesion molecules have been reported to play a
pivotal role. For example, decreased expression of E-cadherin, which
mediates cell to cell adhesion, is correlated with the metastatic or
invasive phenotype of gastric cancer cells (3)
. Another
adhesion molecule, integrin, which mediates cell to cell and cell to
matrix adhesion, has also been known for its involvement in the
peritoneal dissemination of gastric cancer cells; the
ß1 subunit of integrin was reported to be a
promoter (4)
, and the ß4 subunit
was reported to be a suppressor (5)
. Apoptosis-related
genes such as BAG-1, the Bcl-2 family gene, were reported to promote
peritoneal dissemination of gastric cancer cells through an
antiapoptotic effect (6)
. -1,3-Fucosyltransferase
modifies cell surface glycan and facilitates cancer cell adhesion to
the peritoneum via the E-selectin system (7)
.
Previously, Yashiro et al. (8) and Fujihara et al. (9) have established OCUM-2MD3 cells (8) , which have a high potential for peritoneal dissemination when injected i.p. in a nude mice model, and OCUM-2MLN cells (9) , which have a high potential for metastasis to lymph nodes when implanted orthotopically in a nude mice model, from scirrhous gastric cancer cell line OCUM-2M to investigate the mechanism of gastric cancer metastasis. OCUM-2MD3 and OCUM-2MLN cells are the established models to study peritoneal dissemination and lymph node metastasis, respectively, and have been studied extensively both in vitro and in vivo. This model has been applied to describe the promotive effects of CD44H (10) , integrin ß1 (4 , 11) , and factors produced by cocultured fibroblasts (12) in peritoneal dissemination.
Multiple genes are involved coordinately in metastasis, whereas only one gene or a few genes have been considered in most previous reports on metastasis. Moreover, differences in metastatic potential are expected to be due to a combination of differently expressed genes. In this context, gene expression analysis of scirrhous gastric cancer cells with different metastatic potentials in terms of grade and target is extremely relevant to clarify the mechanism of gastric cancer metastasis. In this study, we globally analyzed expression profiles of approximately 6800 genes in OCUM-2M, OCUM-2MD3, and OCUM-2MLN cells by using a high-density oligonucleotide array. By combining this analysis with subsequent confirmation of altered expression in selected genes by Northern blot analysis, we identified differently expressed genes among these cells. Although further functional analysis is necessary, these results will give new insight on the elucidation of the mechanism of gastric cancer metastasis.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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High-Density Oligonucleotide Array Analysis.
One µg of polyadenylated RNA from OCUM-2M, OCUM-2MD3, and OCUM-2MLN
was amplified up to approximately 100 µg of cRNA and hybridized to
the high-density oligonucleotide array (GeneChip HuGeneFL array;
Affymetrix, Santa Clara, CA) as described previously (13)
.
Intensity for each feature of the array was calculated by using
Affymetrix GeneChip version 3.3 software with class ABC mask
file. This so-called mask file is designed to exclude inappropriate
probe pairs and probe sets, which represent introns or reverse
sequences. Average intensity was made equal to target intensity, which
was set to 100, to reliably compare variable multiple arrays. In
calculating the change of average difference, normalization for all
probe sets was performed.
RT-PCR.3
cDNA was synthesized in 20 µl of reaction volume from 5 µg of total
RNA using SuperScript Preamplification System for First Strand cDNA
synthesis system (Life Technologies, Inc., Rockville, MD) and
oligodeoxythymidylic acid primer and diluted up to 80 µl. PCR
was then performed with 1 µl of cDNA for 1 cycle of 94°C for 2 min,
followed by 35 cycles of 94°C for 30 s and 68°C for 3 min
using the primers listed in Table 1
and Advantage cDNA polymerase mixture (Clontech, Palo Alto, CA).
Amplification of the right target DNA was confirmed by mobility on gel
electrophoresis and sequencing after subcloning into pGEM-T easy vector
(Promega, Madison, WI).
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-32P]dCTP-labeled,
random-primed cDNA fragments. Hybridization was performed by using
ExpressHyb hybridization solution mixture (Clontech) according to the
manufacturer’s instructions. The filters were exposed to a BAS imaging
plate overnight and visualized by using a BAS1800 imaging scanner
(Fujifilm, Tokyo, Japan). Signals were quantified by ImageGauge
software version 3.1 (Fujifilm). |
Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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, OCUM-2MD3 showed broader of differently expressed genes in
terms of fold change than OCUM-2MLN. Among the 2680 and 2815 genes
expressed, 63 and 23 genes showed a differential expression level
greater than 4-fold in OCUM-2MD3 and OCUM-2MLN, respectively. To verify
the data, we then performed Northern blot analysis of 100 genes in
total, including 86 genes that showed greater than 4-fold difference by
oligonucleotide array. When changes greater than 2-fold in expression
level by Northern blot analysis are considered significant, consistency
with oligonucleotide array analysis was 49% (42 of 86), whereas no
significant change was seen in 22% (19 of 86), discordant results were
seen in 22% (19 of 86), and undetectable by Northern
blot analysis in two cell lines compared in 7% (6 of 86). Genes
concordant in both analyses are listed in Table 2
, and representative probe tilings after hybridization are shown in Fig. 1B
. We obtained discordant results with genes that showed
elevated expression level in OCUM-2MD3 and OCUM-2MLN by oligonucleotide
array; the ratio of concordance was 70% (25 of 36) for down-regulated
genes and 34% (17 of 50) for up-regulated genes in OCUM-2MD3 and
OCUM-2MLN.
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. Up-regulated genes could be
classified by function as follows: 4 genes for immunity, 2 genes for
trefoil factor, which is a growth factor specific to the digestive
tract, and 2 genes for adhesion. On the other hand, down-regulated
genes could be classified as follows: 6 genes for differentiation
marker of squamous cell lineage, 2 genes for cancer antigen, 2 genes
for insulin-like growth factor protein, 1 gene for apoptosis, 1
gene for extracellular matrix, and 1 gene for the candidate tumor
suppressor gene. Squamous cell differentiation marker gene SPRR2A, one
of the SPRR family genes, was also down-regulated in OCUM-2MD3, as
verified only by Northern blot analysis (Fig. 2A)
.
|
. All five of the up-regulated genes were MHC class
II molecules or MHC class II accessory molecules. MHC class II-DMß
was also up-regulated in OCUM-2MLN, as verified only by Northern blot
(Fig. 2B)
. Because transcription of MHC class II genes and
invariant chain gene is known to be regulated quantitatively by MHC
class II transactivator CIITA (14)
, we next investigated
whether expression of CIITA is up-regulated in OCUM-2MLN cells. CIITA
was not detectable by Northern blot analysis because of its low
expression level, but the expression level of CIITA was relatively
higher by RT-PCR in OCUM-2MLN than in OCUM-2M cells (Fig. 3)
.
|
. Integrin
ß4 and E-cadherin, which play crucial roles in
peritoneal dissemination and invasion of gastric cancer, respectively,
were also down-regulated in both cell lines, as verified by Northern
blot analysis (Fig. 4)
.
|
. MKN45 and
MKN74 have been widely used as a peritoneal dissemination model in nude
mice (6
, 15)
, with a higher potential for peritoneal
dissemination reported in MKN45 (7)
. Ishii et
al. (5)
reported that after injection of 5 x 106 cells of MKN7, MKN74, and MKN45 into
the peritoneal cavity of severe combined immunodeficient mice, 2.3,
41.8, and 149.5 peritoneal nodules were formed, respectively. NUGC-4 is
reported to induce peritoneal metastasis, leading to severe
carcinomatous peritonitis, whereas NUGC-3 did not form a peritoneal
metastasis even at 4 weeks after inoculation (16)
. No
colony of peritoneal dissemination was observed when 1 x 107 OCUM-2MLN cells were injected
i.p.4
Taken together, these cells can be readily classified into two groups:
(a) cells with a high potential for peritoneal dissemination
(OCUM-2MD3, MKN45, MKN74, and NUGC-4); and (b) cells with
low potential or no potential for peritoneal dissemination (OCUM-2M,
OCUM-2MLN, MKN7, and NUGC-3). Although there are no reports on the
peritoneal dissemination potential of GT3TKB in the nude mice system,
we included it in our study because it is one of the cell lines derived
from disseminated nodules on the peritoneum. Trefoil factor 1,
-1-antitrypsin, and galectin 4 showed a high expression level only
in cells with a high potential for peritoneal dissemination and a low
expression level in all of the cells with a low potential for
peritoneal dissemination. On the contrary, cytidine deaminase showed a
reciprocal expression pattern. The expression pattern of integrin
ß4 and E-cadherin did not show any correlation
to peritoneal dissemination potential.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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-1,3-fucosyltransferase, which is essential for
sialyl-Le(X) and sialyl-Le(A) antigen, is reported to be expressed in
the peritoneum, to facilitate the attachment of cancer cells to the
peritoneum, and to promote liver metastasis of some cancers via
E-selectin-mediated adhesion (7
, 17)
. Trefoil factors 1
and 3, growth factors of the gastrointestinal tract that play pivotal
roles in restitution after mucosal injury, are reported to promote cell
growth and motility as well as down-regulate E-cadherin expression
(18
, 19)
. As a result, autocrine production of these
growth factors by cancer cells could be highly advantageous to invasion
and metastasis. Bik induces apoptosis by interacting with Bcl-2
(20)
. Decreased expression of Bik might prolong cell
survival, thereby promoting peritoneal dissemination because
overexpression of BAG-1, a Bcl-2 family gene, can lead to enhanced
peritoneal dissemination of gastric cancer through an antiapoptotic
effect (6)
. Without laminin 
1, which makes a
heterotrimer with other and ß subunits, mature laminin is not
produced, leading to a complete absence of the basement membrane
(21)
. It is reported that decreased expression of laminin,
as often seen in various gastric cancer cell lines, causes basement
membrane fragility (22)
. Thus, reduced expression
of laminin 1 might facilitate tumor invasion by concomitant
incomplete barrier formation. IQGAP1, a negative regulator of
E-cadherin-mediated cell to cell adhesion (23)
, was
down-regulated. A recent study (24)
reported that gastric
hyperplasia are observed in the IQGAP1(-/-) mouse, suggesting another
function of IQGAP1 in relation to overgrowth. In this context, reduced
expression of IQGAP1 might involve cell proliferation rather than
reduced negative regulation of cell to cell adhesion. Down-regulation of the squamous cell differentiation marker gene cluster in OCUM-2MD3 was obvious. Squamous cell differentiation marker included cornified envelope-related genes, CRABP2, and mesothelin. SPRR1A, SPRR1B, SPRR2A, and annexin A1 are all major constituents (25) , and EMP1 was reported to be coexpressed with these four genes (26) . Cornified envelope is observed only in squamous cells such as differentiated keratinocytes, but we could detect expression of one of the cornified envelope-related genes, SPRR1B, in adenocarcinoma cell lines that originated from the breast, pancreas, and colon (data not shown), therefore suggesting possible different roles for this gene cluster other than cornification. Interestingly, these cornified envelope-related genes were also down-regulated in OCUM-2MLN. Thus, reduction of cornification-related genes might have a function that is relevant in metastasis. Coordinate decreased expression of these functionally related genes implicates an upstream regulator; one possible regulator is retinoid because cornified envelope genes are reported to be suppressed by retinoic acid (27) , and CRABP2 mediates retinoic acid signal transduction (28) . Another cell surface marker, mesothelin, which is literally a differentiation marker of mesothelium that covers the peritoneum, regulates the traffic of molecules and cells in and out of the peritoneal cavity (29) . It is probable that reduced expression of mesothelin can alter the adhesiveness of cancer cells to the peritoneum, although there is limited information on the matter of this gene function.
On the other hand, in gastric cancer cell lines with a high potential
for peritoneal dissemination such as MKN45, MKN74, NUGC-4, and
OCUM-2MD3, there was a tendency for galectin 4, -1-antitrypsin, and
trefoil factor 1 to show a high expression level and for cytidine
deaminase to show a low expression level. Whether these genes are
involved in peritoneal dissemination is a matter to be further
investigated.
Up-regulation of MHC class II genes and invariant chain gene in
OCUM-2MLN was extremely intriguing. Expression of these antigen gene
clusters is often observed in a solid tumor, although its significance
to cancer cells is unclear. It was reported that on the surface of
OCUM-2M and OCUM-2MLN cells, MHC class II antigens were not detected by
flow cytometry analysis at all (9)
, suggesting that these
molecules may not be functionally intact or stable. Transcription of
MHC class II genes and invariant chain gene has been considered to be
regulated by MHC class II transactivator CIITA constitutively in B
cells or dendritic cells and inducibly by IFN- in nonlymphoid
tissues (30
, 31)
. In addition, the expression level of
CIITA was reported to be proportional to that of MHC class II genes
(14)
. In this study, a higher expression level of CIITA
was seen by RT-PCR in OCUM-2MLN as compared with OCUM-2M, as predicted.
When analyzed by oligonucleotide array, differential expression of
CIITA between both cell lines was not reliably detected, presumably
because of a subtle change within a low expression level. However, we
could finally detect the difference by deducing an upstream regulator
gene from the expression profile analysis. We believe that this is also
an effective way to make use of array technology and that the
sensitivity of array technology must be improved in the future.
E-cadherin and integrin ß4, genes relevant for
gastric cancer metastasis, were down-regulated in both of the
metastatic sublines of OCUM-2M. E-cadherin is regarded as an invasion
suppressor in gastric cancer and other types of cancer
(3)
, and integrin ß4 has recently
been reported as a suppressor of peritoneal dissemination of gastric
cancer (5)
. Suppressed expression of these genes in the
highly metastatic cells, as we have shown in this study, is in good
concordance with previous reports and indicates that gene expression
change in these cells properly reflects some metastatic
characteristics. In this study, however, these genes showed various
expression patterns among nine gastric cancer cell lines, and no
apparent correlation was observed with peritoneal dissemination
potential. These results clearly show that a complex phenomenon
in vivo such as peritoneal dissemination cannot be explained
by altered expression of a single gene. Thus, the relevance of
exploring the global gene expression profile by using a comprehensive
procedure is obvious.
Although the initial discrepancy between the data by high-density oligonucleotide array and the data by Northern blot was not negligible in this study, the final data presented here were verified by two different methods and must be highly reliable. Oligonucleotide array analysis greatly facilitated clarification of a whole aspect of gastric cancer metastasis by showing the global changes in gene expression and revealing two differently regulated gene clusters, which have not been reported in relation to metastasis. Based on this study, further investigations are now required for all of the genes discussed above to verify their involvement in peritoneal dissemination and lymph node metastasis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by Grants in Aid for
Scientific Research (B) 09557014 and 10470131 and for Scientific
Research on Priority Areas (C) 12217031 from the Ministry of Education,
Science, Sports and Culture (to H. A.). 
2 To whom requests for reprints should be
addressed, at Genome Science Division, Research Center for Advanced
Science and Technology, The University of Tokyo, 4-6-1 Komaba,
Meguro-ku, Tokyo 153-8904, Japan. Phone: 81-3-5452-5235; Fax:
81-3-5452-5355; E-mail: haburata-tky{at}umin.ac.jp
3 The abbreviations used are: RT-PCR, reverse
transcription-PCR; G3PDH, glyceraldehyde-3-phosphate dehydrogenase;
IQGAP1, IQ motif containing GTPase-activating protein 1; SPRR, small
proline-rich protein; CRABP2, cellular retinoic acid-binding protein 2;
EMP1, epithelial membrane protein 1.
4 M. Yashiro, unpublished data.
Received 6/14/00. Accepted 11/29/00.
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REFERENCES |
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2ß1- and 3ß1-integrin in the peritoneal implantation of scirrhous gastric carcinoma.. Br. J. Cancer, 74: 1406-1412, 1996.[Medline]
6ß4 as a suppressor and a predictive marker for peritoneal dissemination in human gastric cancer.. Gastroenterology, 118: 497-506, 2000.[Medline]
-1,3-fucosyltransferase antisense sequences inhibits selectin-mediated adhesion and liver metastasis of colon carcinoma cells.. Cancer Res., 59: 2127-2135, 1999. mediated by the transactivator gene CIITA.. Science (Washington DC), 265: 106-109, 1994.This article has been cited by other articles:
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X174–HaeIII, respectively.