IGFBP7 and Its FuctionsIGFBP7 and Its Fuctions

浙江大学浙江大学 来茂德来茂德等等

IGFBP7IGFBP7 的 抗肿瘤效应的 抗肿瘤效应

结直肠癌发生与发展结直肠癌发生与发展55qq

APCAPC1212pp

Ki-rasKi-ras

1818qqSmad4Smad4DCCDCC

Increase ofIncrease ofgenetic variationgenetic variation

Accumulation of Accumulation of 101044 - 10 - 101212 mutationsmutations

Chromosomal gains or lossesChromosomal gains or losses1010-2-2 per chromosome per generation per chromosome per generation

EarlyEarlyadenomaadenoma

LateLateadenomaadenoma

InvasiveInvasivecarcinomacarcinoma

MetastaticMetastaticcarcinomacarcinoma

NormalNormalepitheliumepithelium

1717ppp53p53

OtherOthermutationsmutations

55qqAPCAPC

1212ppKi-rasKi-ras

1818qqSmad4Smad4DCCDCC

MMRMMR DeficiencyDeficiency错配修复缺陷错配修复缺陷

VogelsteinVogelstein 模型模型 19901990

In 1999, by SSH, We constructed three librariesIn 1999, by SSH, We constructed three libraries

normalnormal adenoma cancerAPC, etc. P53,

etc.

TN A

The derivation of IGFBP7The derivation of IGFBP7

T N

B2

TTTT

TTTTB2

IGFBP7

97%

tester driver

World J Gastroenterol 2001;7(5):726-31

A B C D E MA B C D E M

5’-RACE5’-RACE

Gene card of IGFBP7Gene card of IGFBP7http://www.genecards.org/cgi-bin/carddisp.pl?gene=IGFBP7http://www.genecards.org/cgi-bin/carddisp.pl?gene=IGFBP7

Gene descriptionGene description: : insulin-like growth factor binding protein 7, belongs insulin-like growth factor binding protein 7, belongs

to the IGFBP familyto the IGFBP family Gene aliasesGene aliases: : FSTL2, IGFBP-rP1, MAC25, PSF, FSTL2, IGFBP-rP1, MAC25, PSF,

AGM,TAFAGM,TAF LocationLocation:4q12:4q12

282 AA

32 72 107 156160 264

IGFBP like Kazal likeKazal like Ig like

Signal peptide

I: IGFBP7 in colon cancer tissueI: IGFBP7 in colon cancer tissueIGFBP7IGFBP7 在癌组织中的表达在癌组织中的表达

F=6.29 ， p=0.000; spearman’s rho=0.40,p=0.000

P25

N B A T0

0.5

1

1.5

2

IGFB

P7 A

U

N B A T

p75

p25

Expression of IGFBP7 at mRNA level in colorectal carcinomas (T), adenomas(A), tissue adjacent to tumor(B),and normal tissues(N)

从正常腺瘤到癌表达渐升高从正常腺瘤到癌表达渐升高

T vs. N， 2=12.05 （ df=1 ） , p<0.01

Immunohistochemistry result

11

65

32

46

30

85.5%

60%

60.5%

IHC of IGFBP7 in B and T in the same sample

Clin Cancer Res. 2007;13(17):5082-8

Overexpression of IGFBP7 correlated with favourable prognosis in CRC patients

Survival Functions

Éú´æʱ¼ä

14121086420-2

Cum

Surv

ival

1.1

1.0

.9

.8

.7

.6

.5

.4

BP7T×ÛºÏ

2.00

2.00-censored

1.00

1.00-censored

.00

.00-censored

IGFBP7IGFBP7 高表达预后好高表达预后好

LoVo HCT8 SW1116 RKO HT29 COLO205 Hce8693 CW2 SW620 SW480 Caco2 Control Marker

GAPDH

IGFBP7

IGFBP7 has a low expression in CRC IGFBP7 has a low expression in CRC cell linescell lines

II: The regulation mechanism of II: The regulation mechanism of

IGFBP7 in colon cancerIGFBP7 in colon cancer

Prediction of CpG islands of Prediction of CpG islands of IGFBP7IGFBP7

http://www.ebi.ac.uk/emboss/cpgblot/#andNewcpgseek; http://www.urogene.org/methprimer/index1.html

-355 +803

CpG island:

Length >200bp;

GC% >50%;

Obs./Exp. CpG >0.6

134

the putative promoter region, exon 1 and partial intron 1

Analyzing the methylation status of putative Analyzing the methylation status of putative promoter region, exon1, intron1 in 10 promoter region, exon1, intron1 in 10 cell linescell lines

using Bisulfite Sequencing PCR (BSP)using Bisulfite Sequencing PCR (BSP)

F1 R1F2 R2F3 R3F4

R4

Putative promoter Putative promoter regionregion

exon1exon1

intron1intron1

Methylation pattern of putative promoter Methylation pattern of putative promoter regionregion

HCT8

SW1116

HCE8693

COLO205

HT29

RKO

CW2

SW620

SW480

CACO2

HCT8

SW1116

HCE8693

COLO205

HT29

RKO

CW2

SW620

SW480

CACO2

-335 -329 -302 -298 -291 -286 -271 -251 -237 -223 -218 -214 -206 -202 -191 -185 -182 -174 -163 -160 -147 -146 -144 -142 -133 -131 -125 -117 -112 -108

-99 -88 -83 -69 -67 -58 -54 -49 -46 -35 -32 -28 -23 -18 -9 -7

methylationunmethylation

Intron 1Intron 1

HCT8

SW1116

HCE8693

COLO205

HT29

RKO

CW2

SW620

SW480

CACO2

+505 +509 +529 +532+536+544 +557+560+565 +569 +571+574+580 +585 +587 +599+608 +610+652+654+668 +675+678 +724 +728 +746+772 +801 +812

methylationunmethylation

Exon 1Exon 1

HCT8

SW1116

HCE8693

COLO205

HT29

RKO

CW2

SW620

SW480

CACO2

HCT8

SW1116

HCE8693

COLO205

HT29

RKO

CW2

SW620

SW480

CACO2

+3 +12 +19 +29 +33 +36 +41 +43 +55 +58 +6 +108 +118 +127 +132+144 +156 +175+182 +184+186+188 +193 +211 +215 +217 +220 +226 +233 +235

+244+247 +250+265 +267+270 +283 +293+302+316 +328+331 +336+346 +349+355+368 +375 +382+388 +391 +405+409+422 +424+427 +442+449 +451+490

methylationunmethylation

CW2 Hce8693 SW1116 HCT8 HT29 RKO COLO205 SW620 SW480 Caco2 Control Marker

M U M U M U M U M U M U M U M U M U M U

M, methylated product; U, unmethylated product; M-P, positive control of methylation; U-P, positive control of unmethylation; C, blank control of PCR system

unmethylation

Confirmation using MSPConfirmation using MSP

IGFBP7(+)

ClusterCluster analysis depending on the analysis depending on the methylation status of methylation status of exon 1exon 1

IGFBP7+

RestorationRestoration of IGFBP7 after 5-aza-dC treatment of IGFBP7 after 5-aza-dC treatment

RT-PCR

HT29

SW620COLO205

LoVo

Control Treated

ControlTreated

Immunohistochemistry

Methy-and deMethy sites of IGFBP-rP1Methy-and deMethy sites of IGFBP-rP1gene gene 5’-5’-regionregion

-- ，， controlcontrol ；； ++ ，， treated cellstreated cells ；； Black :methy-per centage Black :methy-per centage

J Pathol. 2007;212(1):83-90.J Pathol. 2007;212(1):83-90.

Methylation of IGFBP7 exon 1:the key regulationMethylation of IGFBP7 exon 1:the key regulationmechanism silencing IGFBP7 expression in CRC cellsmechanism silencing IGFBP7 expression in CRC cells外显子外显子 11 甲基化抑制基因表达甲基化抑制基因表达

Aberrant methylation Aberrant methylation

of IGFBP7 exon 1 in of IGFBP7 exon 1 in

colorectal cancer colorectal cancer

tissuestissues

在结直肠癌中的异常表达在结直肠癌中的异常表达

cases median P25 ~ P75 P

N 46 0.21 0.07 ~ 0.49 <0.001

T 46 0.61 0.30 ~ 0.85

Wilcoxon signed ranks test: Z=-5.131, Wilcoxon signed ranks test: Z=-5.131, PP<0.001<0.001N: matched colorectal normal tissue; T: colorectal cancer tissuesN: matched colorectal normal tissue; T: colorectal cancer tissues

RT-PCR of IGFBP7 in RT-PCR of IGFBP7 in colorectal cancer and matched colorectal cancer and matched normal tissuesnormal tissues

TT

NN

Expression of IGFBP7 protein in Expression of IGFBP7 protein in

colorectal cancer and matchedcolorectal cancer and matched

normal tissuesnormal tissues

0

5

10

15

20

25

30

35

40

N T

case

s

l ow

hi gh

0 1 2 3 P

N 11 26 8 1 0.007

T 6 23 13 4

Wilcoxon signed ranks test: Z=-2.674, Wilcoxon signed ranks test: Z=-2.674, PP=0.007=0.007N: matched colorectal normal tissue; T: colorectal cancer tissues; N: matched colorectal normal tissue; T: colorectal cancer tissues; 0, lack of staining; 1, mild staining; 2, intermediate staining; 3, strong staining0, lack of staining; 1, mild staining; 2, intermediate staining; 3, strong staining

ImmunohistochemiImmunohistochemical stainingcal staining

Expression of IGFBP7 protein in colorectal Expression of IGFBP7 protein in colorectal cancer and matched normal tissuescancer and matched normal tissues

MSP in colorectal MSP in colorectal cancer tissuescancer tissues

N, colorectal normal mucosa; T, colorectal cancer tissues; N, colorectal normal mucosa; T, colorectal cancer tissues;

M, methylated products; U, unmethylated products; M, methylated products; U, unmethylated products;

M-P, positive control of methylation; U-P, positive control of unmethylation; M-P, positive control of methylation; U-P, positive control of unmethylation;

C, blank control of PCR systemC, blank control of PCR system

0

5

10

15

20

25

30

35

40

N Tca

ses

unmethyl ati onmethyl ati on

Methylation status of Methylation status of

IGFBP7 in colorectal IGFBP7 in colorectal

cancer tissuecancer tissue

methylation unmethylation P

N 37 9 0.023

T 28 18

Wilcoxon signed ranks test: Z=-2.268, Wilcoxon signed ranks test: Z=-2.268, PP=0.023=0.023

N: matched colorectal normal mucosa;N: matched colorectal normal mucosa;T: colorectal cancer tissuesT: colorectal cancer tissues

mRNA Expression Methylation status (%)

P

N 0.21 80.4 0.044

T 0.61 60.9

Relationship between Relationship between

IGFBP7 expression and the IGFBP7 expression and the

exon 1 methylation statusexon 1 methylation status

r=-0.210, r=-0.210, PP=0.044=0.044

IHC unmethylation methylation P

Low (0, 1) 15 51 0.004

High (2, 3) 12 14

r=-0.299, r=-0.299, PP=0.004=0.004

III: The biological behaviour of IGFBP7 in III: The biological behaviour of IGFBP7 in

CRC cellsCRC cells 生物学行为生物学行为

IGFBP7 suppressed the growth of RKO IGFBP7 suppressed the growth of RKO cells and SW620 cellscells and SW620 cells 抑制癌细胞生长抑制癌细胞生长

RKORKO SW620SW620*, P=0.0066 IGFBP7-RKO transfectants versus control-vector transfectants,

**, P<0.0001 IGFBP7-SW620 transfectants versus SW620 control-vector transfectants.

***P=0.0108 SW480 versus SW620 cells

IGFBP7 reduced the soft agar colony IGFBP7 reduced the soft agar colony

formation ability of CRC cellsformation ability of CRC cells 减少集落形成减少集落形成

Control-RKO BP7-RKO Control-SW620 BP7-SW620

*, P=0.0004 for IGFBP7-RKO transfectants versus control

**, P=0.0026 for IGFBP7-SW620 transfectants versus control

Control-RKO BP7-RKO

Control-SW620 BP7-SW620

IGFBP7 suppressed the cell growth in soft agar

IGFBP7 induced apoptosis in CRC cellsIGFBP7 induced apoptosis in CRC cells诱导凋亡诱导凋亡

MTT

0

0. 5

1

1. 5

2

2. 5

0 1 2 3 4 5 6

处理时间（天）

(A)

吸光

值

对照2umol / L5umol / L10umol / L20umol / L

AA

BB

AZADCAZADC 抑制结肠癌细胞的生长（抑制结肠癌细胞的生长（ AA ）、促进凋亡（）、促进凋亡（ BB ））

Cancer Biol Ther. 2008;7(12):1896-900.Cancer Biol Ther. 2008;7(12):1896-900.

IGFBP-rP1IGFBP-rP1 inducing senescence inducing senescence 诱导老化诱导老化

Exp Mol Pathol. 2008;85(2):141-5.Exp Mol Pathol. 2008;85(2):141-5.

IGFBP7 was a potential tumor IGFBP7 was a potential tumor suppressor gene in colon cancersuppressor gene in colon cancer

是一个抑癌基因是一个抑癌基因

Cancer Biol Ther. 2007;6(3):354-9

Exp Mol Pathol. 2008;85(2):141-5

Explore the molecular Explore the molecular mechanism……mechanism……

IGFBP7 IGFBP7 transfectantstransfectants ControlControl

? ? What’s different insideWhat’s different inside

Identify the differentially expressed genes in IGFBP7-RKO transfectants versus control

RPRP55

RP6RP6 EVEV66

EVEV55

EVEV77

RP7RP7

vsvs vsvs

vsvs

EV5

RP5

RP7

RP6

EV6 EV7

cluster

Identify the differentially expressed genes using Affymetrix® Identify the differentially expressed genes using Affymetrix® GeneChip® U133 Plus 2.0GeneChip® U133 Plus 2.0

Reproducible in at least 2 clones: Reproducible in at least 2 clones: 9191 genes genes

KEGG pathway analysis: KEGG pathway analysis: MAPKMAPK pathway: pathway: GADD45BGADD45B ，， FOSFOS ，， FLNBFLNB ，， NR4A1NR4A1 ， ， RASA1 RASA1

TGF-TGF- pathway: pathway: SMAD3, CDKN2B, ID1, ID3SMAD3, CDKN2B, ID1, ID3

IGFBP7 could activate IGFBP7 could activate MAPKMAPK pathway and pathway and inhibit inhibit TGF-TGF- pathway.pathway.

Interesting information resides in the chip results:Interesting information resides in the chip results:

Reproductive in 3 clones: Reproductive in 3 clones: 1616 genes genesVerify the chip results(using realtime RT-PCR)Verify the chip results(using realtime RT-PCR)

Analysis of the 16 gene expression in IGFBP7-Analysis of the 16 gene expression in IGFBP7-SW620 transfectants and control. SW620 transfectants and control.

PH 5

Control-RKO （ EV) BP7-RKO (RP)

Comparative 2-DE of BP7-RKO and control8

EV RP EV RP

EV RP

EV RP

EV RPSpot Protein description Sequence

coverage(%)*

Swissprot ID

Theoretical Mr/Pi**

1 Serum albumin 5.74% P02768 69367/6.42

2 Serum albumin 7.97% P02768 69367/6.42

3 Serum albumin 6.86% P02768 69367/6.42

4 pyruvate kinase, muscle 22.45% Q9UK31 6002/7.58

5 Phenylalanyl-tRNA synthetase beta chain 12.56% Q9NSD9 66130/6.39

6 Actin, cytoplasmic 1or 2 33.33% P63261 41793/5.31

7 Actin, cytoplasmic 1or 2 23.20% P63261 41793/5.31

8 60 kDa heat shock protein, mitochondrial precursor

2.96% P10809 61055/5.7

9 60 kDa heat shock protein, mitochondrial precursor

28.52% P10809 61055/5.7

*Sequence coverage was calculated by amino acid count

**Calculated from the database entry without any processing

Unpublished data

The association between IGFBP7 and fasting glucose

IGFBP7 表达与空腹血糖相关

B2

3. 002. 001. 00. 00

Mean

GLU

COSE

6. 4

6. 2

6. 0

5. 8

5. 6

5. 4

5. 2

5. 0

Expression level of IGFBP7

•Endocr Relat Cancer. 2004;11(1):141-8.

y = 0. 1158Ln(x) + 0. 5555R2 = 0. 9789

0

0. 2

0. 4

0. 6

0. 8

1

1. 2

1. 4

0 100 200 300 400 500

(ng/ ml )抗原浓度

OD

(450

nm)

Standard curve

(ng/mL)

Evaluate IGFBP7 level in serum in patients of type 2 diabetes using Elisa

Healthy personsHealthy persons

Frequency of donor’s ageFrequency of donor’s age

ageage

CRC and DM CRC and DM VSVS healthy persons healthy persons

结直肠癌正常人群

50.000

40.000

30.000

20.000

10.000

0.000

IGFB

P-r

P1(u

g/L

)

IGF

BP

-rP

1(µ

g/L

)IG

FB

P-r

P1(

µg/

L)

Healthy persons CRC patientsHealthy persons CRC patients

3T3-L1 preadipoctytes

(×100)

3T3-L1 adipocytes (stain with Oil Red-O) (×100)

3T3-L1 adipocytes

(×100)

IGFBP7 inhibit insulin-stimulated 2-deoxyglucose (DOG) Uptake in 3T3-L1 adipocytes

Metabolic syndrome is Metabolic syndrome is reversiblereversible

代谢综合征是二十一世纪流行病，可逆代谢综合征是二十一世纪流行病，可逆

112233

44 556677

ALSALS

IGF-IIGF-I insulininsulin

extracellularextracellular

??intracellularintracellular

IGFBP-RIGFBP-R

IGFBP-rpRIGFBP-rpRIGF-IRIGF-IR Insulin RInsulin R

MAPKMAPK PI3kPI3k

Mechanism of IGFBP-rP1Mechanism of IGFBP-rP1Burger et al. Eur J Cancer, 41: 1515-1527, 2005Burger et al. Eur J Cancer, 41: 1515-1527, 2005

IGFBP7 may be a molecule contribute to insulin resistance, which may play important roles in the initiation and development of type 2 diabetes.

可能参与 2 型糖尿病的发生和发展

•Unpublished data

IGFBP7 binds insulin with high affinity:IGFBP7 binds insulin with high affinity: 500 fold higher than IGFBP1-6 does.500 fold higher than IGFBP1-6 does.

What’s the binding structure of IGFBP7 to insulin?What’s the binding structure of IGFBP7 to insulin?

Character of IGFBP7Character of IGFBP7

J Biol Chem. 1997;272(49):30729-34.

amino sequence: 172-176amino sequence: 172-176 ，， 196-201196-201 ，， 217-220217-220 ，， 235-244235-244

Predicting the binding domain of IGFBP7 to Predicting the binding domain of IGFBP7 to insulin:insulin:

ATGGAGCGGCCGTCGCTGCGCGCCCTGCTCCTCGGCGCCGCTGGGCTGCTGCTCCTGCTCCTGCCCCTCTCATGGAGCGGCCGTCGCTGCGCGCCCTGCTCCTCGGCGCCGCTGGGCTGCTGCTCCTGCTCCTGCCCCTCTCCTCTTCCTCCTCTTCGGACACCTGCGGCCCCTGCGAGCCGGCCTCCTGCCCGCCCCTGCCCCCGCTGGCTCTTCCTCCTCTTCGGACACCTGCGGCCCCTGCGAGCCGGCCTCCTGCCCGCCCCTGCCCCCGCTGGGCTGCCTGCTGGGCGAGACCCGCGACGCGTGCGGCTGCTGCCCTATGTGCGCCCGCGGCGAGGGCGGCTGCCTGCTGGGCGAGACCCGCGACGCGTGCGGCTGCTGCCCTATGTGCGCCCGCGGCGAGGGCGAGCCGTGCGGGGGTGGCGGCGCCGGCAGGGGGTACTGCGCGCCGGGCATGGAGTGCGTGAAGAGCAGCCGTGCGGGGGTGGCGGCGCCGGCAGGGGGTACTGCGCGCCGGGCATGGAGTGCGTGAAGAGCCGCAAGAGGCGGAAGGGTAAAGCCGGGGCAGCAGCCGGCGGTCCGGGTGTAAGCGGCGTGTGCGTCGCAAGAGGCGGAAGGGTAAAGCCGGGGCAGCAGCCGGCGGTCCGGGTGTAAGCGGCGTGTGCGTGTGCAAGAGCCGCTACCCGGTGTGCGGCAGCGACGGCACCACCTACCCGAGCGGCTGCCAGCTGCGGTGCAAGAGCCGCTACCCGGTGTGCGGCAGCGACGGCACCACCTACCCGAGCGGCTGCCAGCTGCGCGCCGCCAGCCAGAGGGCCGAGAGCCGCGGGGAGAAGGCCATCACCCAGGTCAGCAAGGGCACCTCGCCGCCAGCCAGAGGGCCGAGAGCCGCGGGGAGAAGGCCATCACCCAGGTCAGCAAGGGCACCTGCGAGCAAGGTCCTTCCATAGTGACGCCCCCCAAGGACATCTGGAATGCGAGCAAGGTCCTTCCATAGTGACGCCCCCCAAGGACATCTGGAATGTCACTGGTGCCCAGGTCACTGGTGCCCAGGTGTAGTGTACTTGAGCTGTGAGGTCATCGGAATCCCGACACCTGTCCTCATCTGGAACAAGCTTGAGCTGTGAGGTCATCGGAATCCCGACACCTGTCCTCATCTGGAACAAGGTAAAAAGGGGTCAGTAAAAAGGGGTCACTATCTATGGAGTTCAAAGGACAGAACTCCTGCCTGGTGACCGGGACAACCTGGGAGTTCAAAGGACAGAACTCCTGCCTGGTGACCGGGACAACCTGGCCATTCAGACCGCCATTCAGACCCGGGGCGGGGTGGCCCAGAAAAGCATGAAGTAACTGGCTGGGTGCTGTGGCCCAGAAAAGCATGAAGTAACTGGCTGGGTGCTGGTATCTCCTCTAAGTAAGGAAGATGCTGGGTATCTCCTCTAAGTAAGGAAGATGCTGGAAGAATATGAGTGCCATGCATCCAATTCCCAAGGACAGGCTTCAGCATCAGCAAAAATTACAGTGGTGAATATGAGTGCCATGCATCCAATTCCCAAGGACAGGCTTCAGCATCAGCAAAAATTACAGTGGTTGATGCCTTACATGAAATACCAGTGAAAAAAGGTGAAGGTGCCGAGCTATAATGATGCCTTACATGAAATACCAGTGAAAAAAGGTGAAGGTGCCGAGCTATAA

CN P

W

Prote

in M

arke

r

Who

le BL2

1 lys

ate

With

out W

Super

nata

nt o

f

sonic

ated

BL2

1

Precip

itate

of

sonic

ated

BL2

1

Purifie

d fu

sion

prot

ein

W-p

ET28a

Prote

in M

arke

r

Who

le BL2

1 lys

ate

With

out I

Super

nata

nt o

f

sonic

ated

BL2

1

Precip

itate

of

sonic

ated

BL2

1

Purifie

d fu

sion

prot

ein

I-pET41

a

Prote

in M

arke

r

Who

le BL2

1 lys

ate

With

out 0

1

Super

nata

nt o

f

sonic

ated

BL2

1

Precip

itate

of

sonic

ated

BL2

1

Purifie

d fu

sion

prot

ein

01-p

ET28a

Prote

in M

arke

r

Who

le BL2

1 lys

ate

With

out 0

2

Super

nata

nt o

f

sonic

ated

BL2

1

Precip

itate

of

sonic

ated

BL2

1

Purifie

d fu

sion

prot

ein

02-p

ET41a

W-pET28a(+) P-pET41a(+)

N-pET28a(+) C-pET41a(+)

Express the fragments of IGFBP7Express the fragments of IGFBP7

W P N C

Insulin

SDS-PAGEcut the gel at 6KD

transmembrane

Incubated with

fusion proteinwith His-tag

wash

Incubated with His-tag Ab

wash

Incubated with secondary Ab

For odssey

Analyze the binding affinity of the IGFBP7 fragments to insulinAnalyze the binding affinity of the IGFBP7 fragments to insulin

正在对关键氨基酸进行鉴定正在对关键氨基酸进行鉴定

Conclusions Conclusions 1.The expression of IGFBP7 was upregulated in CRC The expression of IGFBP7 was upregulated in CRC

tissue. Overexpression of IGFBP7 correlates with tissue. Overexpression of IGFBP7 correlates with

favourable prognosis in CRC patients.favourable prognosis in CRC patients.

2.Methylation of exon1 was the key regulating mechanism Methylation of exon1 was the key regulating mechanism

of IGFBP7.of IGFBP7.

3. IGFBP7 played potential tumor suppressor role in IGFBP7 played potential tumor suppressor role in

colorectal carcinogenesis.colorectal carcinogenesis.

4.The patients with insulin resistance are associated with higher incidence of some cancers.The serum IGFBP7 The serum IGFBP7 level was higher in type 2 diabetes and colorectal cancer level was higher in type 2 diabetes and colorectal cancer patients. IGFBP7 may be a molecule contributing to patients. IGFBP7 may be a molecule contributing to insulin resistance.insulin resistance.

GrantsGrants China National “973” program China National “973” program （（ 2007CB914302007CB91430

44 ））

the National Scientific Foundation of China the National Scientific Foundation of China

(30200333, 30570840, 30770989, 30900236)(30200333, 30570840, 30770989, 30900236)

Zhejiang Natural Science Foundation of China   Zhejiang Natural Science Foundation of China   （（ D2080011D2080011 ））

Persons contributed to the researchDepartment of PathologyDepartment of Pathology, ,

Zhejiang UniversityZhejiang University

Dr. Maode LaiDr. Maode Lai

Dr. Minjie LuoDr. Minjie Luo

Dr. Lina ShaoDr. Lina Shao

Dr. Jie LinDr. Jie Lin

Dr. Wenjing RuanDr. Wenjing Ruan

Dr. Yu MaDr. Yu Ma

Dr. Fangying XuDr. Fangying Xu

Lipei WangLipei Wang

Haibing WangHaibing Wang

Youzhao LiYouzhao Li

……

Department of ChemistryDepartment of Chemistry, ,

Zhejiang UniversityZhejiang University

Dr. Tao WuDr. Tao WuDr. Xin Dr. Xin ChenChen