ICANCERRESEARCH56. 325-329.January15. 19961
Expression of a-1,3-Fucosyltransferase Type IV and VII Genes Is Related to Poor
Prognosis in Lung Cancer
Jun-ichi
Ogawa,1 Hiroshi Inoue, and Shirosaku
Koide
First Department ofSurgerv. School ofMedicine, Tokai University, Bohseidai, Isehara, Kanagawa, 259-11, Japan
MATERIALS
ABSTRACT
To date, five a-1,3-fucosyltransferasegenes(Fuc-Till, IV, V, VI, and
Materials.
AND METHODS
Three hundred thirty-three consecutive patients with lung can
cer who had undergonecurativetumor resectionand lymph nodedissection
the synthesisof sialyl Lewis x and the prognosisof lung cancer,PCR from 1980 to 1993 were included in this study. Staging was according to the
amplificationof five fucosyltransferase
genesand immunohistochemical AmericanJoint Committeeon CancerThM classification(17). Patientswith
staining of sialyl Lewis x were performed in 333patientswith lung cancer positive surgical margins were excluded. Procedures at the time of surgery
whounderwentsurgicalresectionfrom 1980to 1993.The frequenciesof were the same for all patients. Of the patients with non-small cell carcinoma,
none with stage I or II disease received adjuvant therapy. Patients with stage ifi
Fuc-TJIIIV, Fuc-TVI, Fuc-TIV, and Fuc-TVJI expression were 9%, 26%,
VI!) have been cloned. To examine the role of a-1,3-fucosyltransferase
75%, and 66%, respectively.
The frequency
in
disease received postoperative
of sialyl Lewis x expression
(75%) was comparable to Fuc-TIV and Fuc-TVII expression.However,
the grading
of sialyl
Lewis x staining
correlated
only with the grading
of
embedded blocks (18). Three 3(L@m-thick
Fuc-TVII gene amplification. Survival of the patients whose tumors
showed strong expression of Fuc-TIV and/or FucT-Vil
shorter
than
that
of the patients
whose tumors
proteinase K (200
various human cancer cells. Its expression plays an important role in
E-selectin-mediated adhesion to activated endothelium (1—3),leading
to hematogenous metastasis of cancers (4). Fuc-Ts are thought to be
key enzymes which regulate synthesis of SLex. Up to now, at least
three distinct types of human Fuc-Ts can be distinguished by their
enzymatic specificity (5), and some of their genes have been cloned
(6—12).The Lewis type a-l,3/l,4-fucosyltransferase, found in kidney,
gallbladder, and milk, is known to catalyze the transfer of fucose to
both type 1 and type 2 chain-based structures. Fuc-TIII corresponds to
this Lewis type. The myeloid type Fuc-T, found in leukocytes and
the transfer
of fucose
to type 2 chain-based
Pure Chemicals,
Osaka, Japan) were added.
amplified
(positions
from Fuc-Till
and
Fuc-TV were 447 and 486 bp, respectively. Fuc-TIV sense, 5'-GCITGC
CCGAAATI'GGQcTCCTGCACAC-3'
(positions 807—833)and antisense,
(positions
1099-1125).
The sizeof the fragmentamplified was319 bp. Fuc-TVI sense,5'-CTCAA
GACGATCCCACTGTGTAC-3' (positions 110-132) and antisense,5'CAGCCAGCCGTAGGGCGTGAAGATGTCGGA-3'
(positions
484-513).
The size of the fragmentamplified was404 bp. Fuc-TVII sense,5'-CTCG
GACATC1TrGTGCCCTATG-3' (positions 438-460) and antisense,5'CGCCAGAA'1TFCTCCGTAATGTAG-3'(positions702-725). The size of
the fragmentamplified was288 bp. One @xg
genomicDNA wasamplified in
a 50-pi reactionmixture containing 25 pmol of primers, deoxynucleotide
triphosphates
(2.5 mM), 10 mM Tris-HC1 (pH 8.0), 50 mM KCI, 1.5 mM MgCI2,
Glass,Funabashi,Japan).Eachcycleconsistedof 1mm denaturationat 95°C,
1mmannealingat 60°C,
and2 mmextensionat 72°C.
Electrophoresisof PCR
products (10 @tl)on a 2% agarosegel containing ethidium bromide (0.5
to the SLex expression and also to the correlation with prognosis
remains to be answered. Therefore, we examined the expression of
five Fuc-T genes in patients with lung cancer.
The costsof publicationof this article weredefrayedin part by the paymentof page
charges. This article must therefore be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
To whom requests for reprints should be addressed. Phone: 463-93-1 121; Fax:
463-95-7567.
SLex,
sialyl
@g/ml)
wasdoneto evaluatethesizeof generatedfragments.Positivecontrolreactions
were performed
with
DNA
template
from
the same patient
whose DNA
templatestronglyexpressedall of the Fuc-T genes(Fig. 1, case1). Negative
control reactions were done without DNA template. The grading of gene
expression was as follows: (—), no expression; (+), weak expression in which
Received 8/29/95; accepted I 1/7/95.
ferase
typesIll—VII.
sense, 5'-CAGCCAGCCGTAGGGCGTGAAGATGTCGGA-3'
487—516/526—555). The size of the fragments
Forty cycles of amplification were performed with a thermal cycler (Iwaki
In a previous study, we have demonstrated that immunohistochem
ical expression
of SLex correlates with the prognosis in lung cancer
(15, 16). However, the question of which fucosyltransferase is related
are:
ethanol,dried thoroughly,and resuspended
in 20 mrsiTris-HC1solution(pH
7.5) to a final DNA concentrationof 1
The DNA concentrationwas
determinedspectrophotometrically.
PCR Analysis of Fuc-T. The primersequences preparedfor PCR ampli
fication of Fuc-T were as follows: Fuc-TllhIFuc-TV sense, 5'-CTGCTGGT
GQCTGTGTGmCTfCTCCFAC-3'
(positions 70-99/70-99) and anti
0.01%gelatin,and 1.5 units Taq polymerase(TakaraSchuzo,Otsu,Japan).
thatare not sialylated.
used
volumes 100%cold ethanol,incubationat —
80°Cfor at least 30 mm, and
centrifugation for 20 mm at 15,000 X g. The pellet was washed with 75%
5'-CCAGAAGGAGGTGATGTGGACAGCGTA-3'
structures,
but is much less active on sialylated substrates. Fuc-TIV corresponds
to this myeloid type. The plasma-type Fuc-T, found in plasma and
liver, transfers fucose to type 2 chain-based structures whether they
are sialylated or not. Fuc-TV or Fuc-TVI, which are very similar in
their structures, correspond to this plasma type. In addition to the
aforementioned Fuc-T, a novel one designated Fuc-TVII recently has
been cloned from human leukocytes (13, 14). This enzyme can
efficiently utilize sialylated type 2 chain-based acceptorsbut not those
abbreviations
@g/ml;WaKO
with 1 volume chloroform. The DNA was precipitated by the addition of 2.5
The SLex2 carbohydrate structure has been found on the surface of
2 The
for
Incubationwasovernightat 48°C.Nucleic acid wasextractedtwice using 1
volumephenol:chloroform:isoamylalcohol
(25:24:1) and then extractedonce
INTRODUCTION
@
for 30 mm and centrifuged
5 mm at 15,000x g twice. After discardingthe supernatant,the pellet was
resuspended
in 1 ml 100%ethanolandcentrifugedfor 5 mm at 15,000X g.
Thepelletwaswashedagainwith 100%ethanol,driedthoroughly,and500 @l
buffer (50 mM Tris-HC1,1 mi@iEDTA, and 0.5% Tween 20, pH 8.5) with
participating in the biosynthesisof sialyl Lewis x.
brain, catalyze
sections were prepared from each
immersed in 1 ml xylene at room temperature
either
Fuc-TIV or Fuc-TVII. These results suggest that Fuc-TIV and Fuc-T VII
expression may be of prognostic value among patients with lung cancer by
@
or radiation therapy. Those with
blockaftercuttingawayasmuchof theparaffinaspossible.Thesectionswere
was significantly
did not express
chemotherapy
smallcell carcinomareceivedpreoperative
andpostoperative
chemotherapy.
DNA Extraction. DNA was extracted from formaldehyde-fixed, paraffin
Lewis
x; Fuc-TIll—Vil,
a-1,3-fucosyltrans
PCR productswere visible but much weakerthan the positive control; and
(+ +), strongexpressioncomparableto the positivecontrol.
InununohistochemicalExpressionof SLex. A streptavidin-biotinylper
oxidase complex method using FH6 monoclonal
antibody (kindly
provided by
OtsukaPharmaceutical,Tokyo, Japan)againstsialyl dimeric Lewis x were
performed on thin sliced sections as previously reported (15). Immunohisto
325
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1996 American Association for Cancer Research.
EXPRESSION OF Fuc-T IN LUNG CANCER
Table I Patientcharacteristics
patientsNo.
guished (Fuc-TIII 447 bp versus V 486 bp, Fuc-TIV 3 19bp versus VII
No. of
288 bp), they were in separatelanes.
Relationship between Fucosyltransferaseand SLex Expression.
The frequencies of expression (+) and (+ +) of Fuc-T were 9% for
Fuc-TIII/V, 26% for Fuc-TVI, 75% for Fuc-TIV, and 66% for Fuc
TVH, respectively. The frequencies of Fuc-TIV and Fuc-TVII expres
typesAdenocarcinoma172Squamous
sion were significantly greater than Fuc-TIII/V and Fuc-TVI. The
frequency
of expression (+) and (+ +) of SLex was 75%, which was
18Large cell carcinomaI
carcinoma24Small
cell
comparable to that of Fuc-TIV and Fuc-TVII. However, the grading
carcinoma15Adenosquamous
cell
of SLex staining correlated only with the grading of Fuc-TVII (Table
carcinoma4Stage―I162II40III131a
cell
2; P < 0.01).
Survival According to SLex, Fuc-TIV, and Fuc-TVII Expres
sion. Survival of patientswho had tumorswith SLex (+ +), Fuc-TIV
(+ +), and Fuc-TVII (+ +) expression was significantly shorter than
Stages were in accordance with the AJCC staging system (17).
that in patients with SLex (—) or (+), Fuc-TIV (—) or (+), and
Fuc-TVII (—)or (+) expression, respectively. Survival difference
chemicalstainingwasexaminedin at least1000cellsin five high-powerfields between the patients with (—)and (+) expression of SLex, Fuc-TIV,
(magnification
x 1000). The grading of SLex staining was as follows: (—),
and Fuc-TVII was not significant (Fig. 2). The expression of Fuc
<5% of cells had membraneousstaining;(+), 5—29%
of cells stained;and Till/V and Fuc-TVI did not significantly affect the survival of patients
(+ +), 30%or morecellsstained.NegativecontrolsomittedtheFH6antibody. (data not shown). The 333 patients were divided into four groups
Data Analysis. The frequenciesof geneandSLexexpressionwereevalu
according to their Fuc-TIV and Fuc-TVII expression: group 1, pa
atedusingthe test.Survivalcurveswerecalculatedusingthe Kaplan-Meier
tients
with both Fuc-TIV(—) and Fuc-TVII(—) tumors (n = 54);
method,and statisticalevaluationwas doneusing the log rank test. Patients
group 2, patients with Fuc-TIV(+) and/or Fuc-TVII(+) tumors
who died of causes other than primary lung cancer were censored.
(n = 85); group 3, patients with either Fuc-TIV (+ +) or Fuc
TVII(+ +) tumors (n = 62); and group 4, those with both Fuc-TIV
RESULTS
(+ +) and Fuc-TVII(+ +) tumors (n = 132). Group 3 and group 4
patients had significantly shorter survivals compared with group 1 or
Clinical Characteristics of the Patients. The age, sex, histologi
group 2 patients (P < 0.01). There was no significant survival
cal type, and stages of the patients are shown in Table 1. Of the 333
patients, 131 died of primary lung cancer and 32 died of causesother difference between group 1 and group 2, nor between group 3 and
than lung cancer. The follow-up period for the 152 patients who had group 4 (Fig. 3). Similar results were obtained when tumors were
subdivided according to stagesand histological types. In both stage I
no evidence of tumor recurrence ranged from 21 to 185 (median, 65)
or stage IH disease, or in adenocarcinomas or squamous cell carcino
months.
Expression of Fucosyltransferase Genes. Prior to the experiment, mas, group 3 and 4 patients had significantly shorter survivals than
group 1 and 2 patients (P < 0.01; Fig. 4).
we used four different initial amounts of genomic DNA from the
positive control patient: 1, 10, 100, and 1000 ng. Each specific Fuc-T
gene product was amplified in a dose-dependentmanner by 30, 32, 35, DISCUSSION
37, 40, and 45 cycles of PCR. The specific product reached a plateau
at 45 cycles when 1 @ggenomic DNA was used, whereas we esti
In the biosynthesis of the SLex structure, sialylation precedes
mated gene amplification with 1 @gDNA by 40 cycles of PCR (data
fucosylation because a-2,3-sialyltransferase does not act on fucosy
not shown). Gene amplification of five Fuc-T from eight representa
lated substrates (19). Therefore, the final step in SLex synthesis is
tive patients is shown in Fig. 1. Because amplified fragments of the catalyzed by Fuc-T. To date, five Fuc-T genes have been cloned and
Fuc-TIII and -TV and Fuc-TIV and VII could not be easily distin
their chromosomal locations determined (10, 14, 20). Previously, we
patients333Age
of
64)SexMale231Female102Histological
(yr)32—84
@
(median,
case
bp 1 2 3 4 5 6 7 8 1 2 3
Fig. 1. PCR amplification of fucosyltransferase
genes in eight representative samples. Top, Fuc
TI!!, V. VI, and IV genes; bottom, Fuc-TVII gene.
Left, bp size markers; right, size of amplified prod
ucts in bp. Cases 1—3:
all genes are strongly
486(Fuc-TV),447(ffl)
-L.N.4@$@
319@V)
1oo@
expressed. Fuc-TIII and Fuc-TV fragments can
be distinguished in the latter three lanes at the top
right. Cases4—6:Fuc-TVI, IV, and VII are strongly
expressed. Case 7: Fuc-TIII, V. IV, and VII are
strongly expressed. Case 8: Fuc-TIII, V. and IV are
strongly expressed.
4-288(VU)
326
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1996 American Association for Cancer Research.
EXPRESSIONOF Fuc-T IN LUNG CANCER
expressionFucosyltransferaseFuc-TIII,VFuc-TVIFuc-TIV
Table 2Relationship betweenfucosyltransferase and sialyl Lewis X
(+)(++)Fuc-TVII(—)(+)(++)“(—)(+)(++)(—)(+)(++)TotalSialyI(—)
Lewis x
(—)“
(+)
108
3
(++)
121
3044
8
155
Total75
7
2
1464
85
97
2467
18
14
28
25
31
17
4213
18
4524
30
82
26
8235
58
40
34
11418
76'
16936
28
49
20
6030
78d
118
131
15984
333
a Grades of gene amplification are as follows: (—), no expression; (+), weak expression; (+ +), strong expression.
b Grades of SLex staining are as follows: (—), <5% of cells had membranous staining; (+), 5—29%of cells stained; (+ +), 30% or more cells stained.
( P
@
=
0.22.
d
P values were obtained using a 3 X 3 x2 test.
found that SLex expression correlated with the prognosis of patients
with lung cancer (15, 16). Results similar to the present report were
also described in colon cancer (21). It was reported that highly
metastatic colon carcinoma cells, as compared to their low metastatic
counterparts, bind more efficiently to activated human endothelial
cells through the E-selectin-SLex interaction (22). These results sug
gest that SLex may serve as a ligand for E-selectin and its expression
correlates with the metastatic potential of cancer cells. In this study,
we have shown that patients with tumors which strongly expressedthe
Fuc-TIV and/or Fuc-TVJJ genes have a poor prognosis, and that a
correlation between SLex and Fuc-TVII expression exists. This is in
agreement with the finding that Fuc-TVII can efficiently use a-2,3sialyllactosamines to form SLex (13, 14). It is not clear, however,
whether the correlation between Fuc-TIV expression and prognosis is
related to its role in the synthesis of SLex becauseFuc-TIV reportedly
100
80
a2
@
60
U
.@
40
Sialyl Lewis x (—X84)
E
C.) 20
———.—
SialylLewisx(+)(117)
Sialyl Lewis x (4—f)
(132)
0
100
acts
80
I60
..@
poorly
on a-2,3-sialyllactosamines
(8, 9). Goelz
et al. (23)
reported that, in some cultured cell line transfected with the Fuc-TIV
gene, sialyllactosamines can be fucosylated according to the range of
carbohydrate structures of acceptors,and the SLex structure expressed
is likely to have more polylactosamine content with more than one
fucosylated sites. In fact, the antigen defined by the FH6 monoclonal
antibody used in this study is identified as a SLex carried by difuco
syl- or trifucosyl-type 2 chain as well as a long-type chain (24). It is
40
Fuc-TIV(--)(82)
E
U 20
@-—.—
Fuc-TIV(+)(82)
Fuc-TIV(++)(169)
100 -@
0
@
-i_
80
100
80
-@--.@
60
C,)
60
5)
40
C,,)
U
40
@-@-
Fuc-TVII (—)(110)
———.@
U
Fuc-TIV (—)and VII (—)(54)
U
20
Fuc-TJV
Fuc-TJV
Fuc-TVll(+)(6@)
—
Fuc-TVII
(+÷)
(157)
0
0—
0
5
Year
(+)
and/or
VII
(+)
(85)
@—
Fuc-TIV
(+-,-)
and
VII
(++)
(132)
—...—...—
.
1
.
2
(++)
or
VII
.
3
(++)
(62)
.
4
5
Year
Fig. 2. Survival according to sialyl Lewis x. Fuc-TIV, and Fuc-TVII expression.
Survival curves were calculated using the Kaplan-Meier method, and statistical evaluation
Fig. 3. Survival according to Fuc-TIV and Fuc-TVII expression. Each tick mark
representsa patient who is alive or died of causesother than primary lung cancer. Group
1: Fuc-TIV(—)and Fuc-TVII(—);Group2: Fuc-TIV(+) and/orFuc-TVII(+); Group 3:
wasdoneusingthe log rank test.P < 0.01: SLex(+) versus(+ +), Fuc-TIV(—)versus Fuc-TIV(+ +) or Fuc-TVH(+ +); Group 4: Fuc-TIV (+ +) and Fuc-TVII(+ +).
(+ +) Fuc-TIV(+) versus( + +), Fuc-'I'VII(—)versus(+ +); P < 0.02: SLex(—)versus P < 0.01: group 1 versus3, group 1 versus4, group 2 versus3, group 2 versus4; not
(++); P < 0.03: Fuc-TVII(+) versus(++).
statistically significant: group I versus 2, group 3 versus 4.
327
Downloaded from cancerres.aacrjournals.org on June 17, 2017. © 1996 American Association for Cancer Research.
EXPRESSIONOF Fuc-T IN LUNG CANCER
pression in our study may reflect the retrodifferentiation of cancer
cells.
Expression of the Fuc-TIV and Fuc-TVII genes correlate with
poor prognosis by participating in the synthesis of SLex and may
be of prognostic value in lung cancer. It will be important to
understand the role of fucosyltransferases
in the formation of
SLex, since this might lead to anticancer strategies based on the
down-regulation of SLex expression via inhibition of fucosyltrans
ferase activity.
100
80
60
C,)
5)
40
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Expression of α-1,3-Fucosyltransferase Type IV and VII Genes Is
Related to Poor Prognosis in Lung Cancer
Jun-ichi Ogawa, Hiroshi Inoue and Shirosaku Koide
Cancer Res 1996;56:325-329.
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