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SIGNIFICANCE AND RELATIONSHIP BETWEEN CRIPTO-1 AND P-STAT3 EXPRESSION IN GASTRIC CANCER AND PRECANCE

Sig n i can ce an d re la t io n s h ip b e tw een Crip to-1an d p-STAT3 ex p res sio n in g a st ric ca n ce r a n d p re ca n ce ro u s lesio n s

Jian-G uo Zhang,Jing Zhao,Y an X in

Jian-Gu o Zhang,Jing Zhao,Y an X in,The Fourth Laboratory of Cancer Institute,Department of Tumor Pathology of General Surgery Institute,the First Af liated Hospital of China Medical University,Shenyang110001,Liaoning Province,China

A uthor contributions:Zhang JG performed the whole experi-ment,statistical analysis and wrote the manuscript;Xin Y designed the study,provided financial support,vital experi-mental equipments for this work and was involved in revising the manuscript;Zhao J participated in the experiment. Supported by National Natural Science Foundation of China, No.30973503and Special Fund for Climbing Scholars of Universities in Liaoning Province,China,2009-2010 Correspondence to:Y an X in,Professor,The Fourth Laboratory of Cancer Institute,Department of Tumor Pathology of General Surgery Institute,the First Af liated Hospital of China Medical University,Shenyang110001,Liaoning Province,

China.yxin@https://www.wendangku.net/doc/593686685.html,

T elephone:+86-24-83282351Fax:+86-24-83282375 Received:October28,2009Revised:December11,2009

A ccepted:December18,2009

Published online:February7,2010

Ab stra c t

AIM:To exp lore th e relation sh ip b etw een Crip to-1 (CR-1)and tyrosin e phos phorylation STA T3(p-STA T3) exp ressions in gastric cancer(GC)an d g astric carcino-gensis and met as tasis.

METHO DS:Th e PV9000immun ohistochemical method was used to detect th e expres sion of CR-1and p-STA T3 in178cases of GC,95match ed normal gast ric mucosa, 40chronic atrophic g as tritis(CA G),48intestin al meta-plasia(IM)an d25dys plasia(DYS).

RESULT S:The po sitive ra tes of CR-1an d p-STAT3 express io n w ere sign ifican tly high er in CAG(65.0% and60.0%),in IM(83.3%an d77.1%),DYS(80.0% and68%)an d GC(71.3%and60.1%)than in normal

(3%%,<5), y T x f R ST T3(3% 66%)y G y

no d e me ta st as is t h an in t h os e w it h ou t met as t as is

(53.1%an d42.9%,P<0.05).CR-1expressio n was

also related to h ist olog ical an d Lauren’s types of GC (P<0.001).F u rth ermore,th ere was p ositive relation-ship between CR-1and p-STA T3expressio ns in GC(r k=

0.189,P=0.002).

CO NCLUSION:The up-regu lation of C R-1and p-STA T3 may play important roles in gastric carcin ogenesis and lymph n ode metast as is.CR-1and p-STA T3exp ression in GC was pos itively correlated,and the relevant molecular mechanism requires further investig ations.

2010Baishide ng.A ll rights re se rved.

Key wor ds:Cripto-1;Phos pho rylat ion STAT3;Gastric cancer;Precan cero us lesions;Immun ohis toch emistry Peer reviewers:Masanori Hatakeyama,MD,PhD,Professor, Department of Microbiology,University of T okyo,7-3-1Hongo, Bunkyo-ku,Tokyo113-0033,Japan;Vittorio Ricci,MD,PhD, Department of Physiology,Human Physiology Section,University of Pavia Medical School,Via Forlanini6,Pavia27100,Italy;

Nathalie Perreault,PhD,Associate Professor,Department of Anatomy and Cell Biology,University of Sherbrooke,300112th

A venue North,Sherbrooke,J1H5N4,Canada

Zhang JG,Zhao J,Xin Y.Signi cance and relationship between Cripto-1and p-STA T3expression in gastric cancer and precan-cerous lesions.W orld J Gastroenterol2010;16(5):571-577

A vailable from:URL:https://www.wendangku.net/doc/593686685.html,/1007-9327/full/

v16/i5/571.htm DOI:https://www.wendangku.net/doc/593686685.html,/10.3748/wjg.v16.i5.571

I NTR ODUCTION

Human Cripto-1(CR-1),the founder member of the epider mal growth factor-Cripto-FRL1-Cr yptic family,plays an important role during early embryonic

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On line Su b mission s:h ttp://w ww.w j g n https://www.wendangku.net/doc/593686685.html,/1007-9327o f ce w jg@w jgn https://www.wendangku.net/doc/593686685.html,

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gastric mucos a4.2and41.1P0.0res pec-tivel.he e pres sion s o C-1and p-A78. and.7were signi cant l high er in C with l mph

development and cellular trans ormation.C-1is also an oncogenic growth actor involved in t umorigenesis through in uencing cell proli eration survival migration 71eb ru ar72010olum e1ssue

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and inv asion [2-4].CR-1is absent or in low levels in normal tissues but over-expressed in most malignant tumors,such as breast,colon,stomach,pancreas,lung,cervix and ov ary cancers,which is being assessed as a tumor-speci c target for immunotherapy [1,5].STAT3,a well recognized oncogene,is an important member of the STAT family that are normally inactive within the cytoplasm and become activated by ty rosine phosphory lation in response to cytokines and growth factors [6].Its sig nal pathway is closely associated with the proliferation,differentiation and apoptosis,and constant activation of STAT3can promote cell proliferation and carcinogenesis [7,8].Given the importance of CR-1over-expression and STAT3activation in carcinogenesis,we investigated the expression and clinic opath ological significance of CR-1and phosphory lation STA T3(p-STA T3)in gastric cancer (GC),and also explored the relationship between abnormal expressions of the two oncoproteins in GC.

M A TER IA LSA NDMETH OD S

Clinicopathologicaldata and tissue microarray construction

Surgically resected GC specimens were collected from the First Affiliated Hospital of China Medical Univer-sity ,including 178cases of GC,95matched normal gastric mucosa (obtained at >5cm apart from the edge of primary tumor focus),40chronic atrophic gastritis (CA G ),48intestinal metaplasia (IM),and 25dysplasia (DYS).There were 121males and 57females.The mean age of patients was 61years.According to Borrmann ’s classi cation,gross ty pes of primary tumors were clas-sified as follows:4cases of Borrmann Ⅰ,22cases of Borrmann Ⅱ,140cases of Borrmann Ⅲ,and 12cases of Borrmann Ⅳ.In the lig ht of the WHO ’s histological classi cation of GC,178cases were classi ed as follows:2papillary adenocarcinoma,9well and 65moderately and 74poorly differentiated adenocarcinoma,3undif-ferentiated adenocarcinoma,19mucinous adenocarci-noma and 6signet ring cell carcinoma.Samples were xed in 10%formalin,embedded in paraf n,cut into 4μm thick sections and constructed in blocks for tissue microarray .All the samples were evaluated by two expe-rienced pathologists for diag nosis.None of the patients had received chemotherapy or radiation therapy preop-eratively .

I mmunohistochemistry

Expression of CR-1and p-STA T3in GC,precancerous lesions and normal gastric mucosa were detected using an IHC method.The PV -9000kit was purchased from Beijing Zhongshan G olden Bridge Biote chnology Company .Mouse monoclonal antibody against human CR-1w as from the R&D sy stems (work ing dilution 1:80).Rabbit monoclonal antibody against human p-STAT3was from the Signalway Antibody (working dilution 5)f ’F ,w ere treated with 0.01mol/L phosphate-buffered saline instead of primary antibodies.

I mmunohistochemical staining evaluation

Specific immunoreactivity of CR-1protein w as located in the cy toplasm,w hile p-STAT3protein was located in the nucleus and cy toplasm.Two hundred cells from tw o selected representative elds of each section were counted by tw o independent observers for the determination of their immunostaining intensity .Staining intensity (A)was classified as 0(negative),1(weak),2(moderate)and 3(strong ).The percentage of positive cells (B)examined in 200cells were divided into 0(<5%),1(5%-25%),2(26%-50%),3(51%-75%)and 4(>75%).According to the product of A and B,the IHC result w as classi ed as 0,negativ e (-);1-4,weakly positive (+);5-8,moderately positive (++)and 9-12,strong ly positive (+++).

Statistical analysis

Statistical analy sis was performed using SPSS 11.5Pack-age,and χ2

test,Fisher ’s exact test and Kendall ’s tau-b test w ere used to differentiate the rates of different groups and test the correlation between the tw o factors.P <0.05w as considered statistically signi cant.

R ES UL T S

E xpression of CR-1in normalgastric mucosa,CA G,IM ,

D Y S and GC

The immunoreactivity of CR-1protein was located dif-fusely in the cy toplasm.The positive rates of CR-1pres-ence in CA G (65.0%,26/40),IM (83.3%,40/48),DYS (80.0%,5/25)and GC (71.3%,127/178,Fig ure 1A)were significantly higher than that in normal gastric mucosa (43.2%,41/95,Figure 1B),respectively ,P <0.05;there w as no statistically signi cant difference in CR-1expres-sion between DY S and GC (P =0.246),but the positiv e rate of CR-1in IM was sig ni cantly higher than that in GC (T able 1).

E xpression of p-ST A T 3in normal gastric mucosa,CAG ,I M ,D Y S and G C

The immunoreactivity of p-STAT3protein was located in the nucleus and cytoplasm.The positive rates of p-STAT3expression in CAG (60%,24/40),IM (77.1%,37/48),DYS (68.0%,17/25)and GC (60.1%,107/178,Figure 1C)were significantly higher than that in nor-mal gastric mucosa (41.1%,35/95,Fig ure 1D),respec-tively ,P <0.05.There was no signi cant difference in p-STAT3ex pression among IM,DYSand GC (P =0.087,P =0.103,Table 2).

Correlation betw een CR-1,p-ST A T3ex pression and clinicopathological features of GC

T ables 3and 4show ed the correlation of immunohisto-(I )x f R ST T3S y 5F y ,|V 6|I 5|

W G |j Zhang JG et al.Cripto-1and p-STA T3expression in gastric cancer

1:2.All procedures were implemented according to the manu acturer s instructions.or negative controls sections

chemical HC e pression o C -1and p-A with clinicopathological parameters.tatistical anal sis showed

72eb ru ar 72010olum e 1ssue J w ww.w gn https://www.wendangku.net/doc/593686685.html,

the expression of CR-1was related to histological

differentiation (P <0.001),Lauren ’s ty pes (P <0.001)y (=6)(F ),f ,B rmann ’s classi cation of GC.There was no relation be-tw een p-STAT3expression and gender,age,Borrmann ’s f ,y L ’y ,ST T3x f y 53F y ,|V 6|I 5|

W G |j Fi gure 1Expressi on ofCripto-1(C R-1)an d pho sphory lati on ST A T3(p-STA T3)in gastric cancer (GC)(A,C)and normal gastric mu cosa (B,D).IH C PV 9000×400.

A B

C D

Fi g ure 2E xpres sion of CR-1and p-ST A T 3in GC without ly mph node m etas tas is (A ,B)and with lymph node metas tasis (C,D).IH C PV9000×200.

A B

C D

Zh ang JGet al.Cripto-1and p-STA T3expression in gastric cancer

and l mph node metastasis P 0.00igure 2A and C but not related to the age and gender o patients or or-classi ication histological t pes or auren s t pes but p-A e pression was signi icant l higher in t umors

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with ly mph node metastasis (66.7%)than in those without metastasis (42.9%),P <0.05(Figure 2B and D).Correlation betw een ex pressions of CR-1and p-ST A T 3in G C

The positive relationship was observed between CR-1and p-STAT3expression in GC (r k =0.189,P =0.002)(Table 5).

DI SCUS SION

Human CR-1,also known as teratocarcinoma-derived growth factor-1(TDG F-1),was originally isolated and cloned from a human NTERA-2teratocarcinoma cDNA library and w as classified among the epidermal growth factor (EG F)family of peptides due to amino acid se-quence similarities within the EGF-like domain [9].CR-1maps to human chromosome 3p21.3and encodes a 188-amino acid g ly cosylphosphatidylinositol-linked gly -coprotein.CR-1protein contains a signal sequence,a characteristic EGF-like domain,a second cysteine-rich region motif (CFC domain),and a hy drophobic COO H-terminus [1].Several ndings suggested that CR-1can spe-ci cally bind to Gly pican-1,a membrane-associated hepa-ran sulfate proteogly can,and activ ate the ty rosine kinase c-Src,trigg ering the mitogen-activ ated protein kinase and Akt signaling pathway s and then promote cell prolifera-tion,surv iv al,mig ration,and inv asion [4,10].In addition,by f x f β(TGF β),R TGF β

,TGF βof cell growth in various target tissues [11,12].Disruption of

their signaling was associated with carcinogenesis.CR-1may be a potential target for therapy in human malignan-cies [5].In fact,anti-CR-1antisense oligonucleotides or neutralizing blocking anti-CR-1monoclonal antibodies hav e been shown to strong ly inhibit the in v itro and in v iv o growth of human breast,colon,ovarian,testicular,and leukemia carcinoma cells [5,13,14].

Bianco e t al [15]determined CR-1plasma levels using a sandwich-ty pe ELISA in 21healthy volunteers,54pa-tients with breast cancer,33patients with colon carcino-ma,and 21patients with benign breast lesions.V ery low levels of CR-1were detected in the plasma of healthy v olunteers (0.32±0.19ng/mL).A significant increase in the levels of plasma CR-1was found in patients with colon carcinoma (4.68±3.5ng/mL)and in patients with breast carcinoma (2.97±1.48ng/mL,P <0.001),indi-cating that measurement of plasma CR-1lev el can help in early detection of malignancies.Similar observations were made in IHC analy sis and real-time rev erse tran-scription-PCR detection.Zhong e t al [16]evaluated CR-1expression in 118cases of GC,and found that the posi-tiv e rate of CR-1was associated with ly mph node metas-tasis,liver metastasis and late TNM stage (P <0.05).Our IHC investigation showed that the expression of CR-1in CAG,IM ,DYSand GC was signi cantly higher than that in normal gastric mucosa,sugg esting the over-expression of CR-1may contribute to malig nant transformation of W R y y f y I 5F y ,|V 6|I 5|

W G |j G roups

CR-1e xpre ssion +→+++(%)

χ2P

-++++++N orma l mucosa 95542311

743.28.394/25.813<0.039a /<0.001

CAG 40141112365.0 4.214/4.1920.239c /0.242

IM 4881819383.39.1690.027

DYS 255136180.013.051/4.1350.005f /0.246g GC

178

5163

71.3

21.236/3.347

<0.001h /0.341i

Normal mu cosa vs CAG;b

N orma l mucosa vs IM;c

CAG vs IM;d

CA G vs DYS;e

IM vs GC;f

N orma l mucosa vs DYS;g

D Y S vs GC;h

N orma l mucosa vs GC;i

CAG vs G C.CR-1:Cripto-1;G C:Ga stric can cer;CA G:Chronic a trophic gastritis;IM:Intest inal me tap lasia ;D Y S:D ysplasia.

G roups

p-S T A T 3e xpre ssion +→+++(%)

χ2P

-++++++N orma l mucosa 95562511

341.118.4050.012a,b /<0.001c

CAG 4016222060.00.113a,d /0.003a,e

IM 4811286377.1 6.6040.087f

DYS 25878268.0 6.2590.022a,g /0.103h GC

17871

60.1

10.322/7.220

0.016i /0.065j

Fisher ’s exact t est;b

N ormal mu cosa vs CA G;c

N ormal m ucosa vs IM;d

CA G vs IM;e

CAG vs DYS ;f

IM vs G C;g

N orma l mucosa vs DYS ;h

D YS vs G C;i

N orma l

mucosa vs G C;j

CAG vs G C.

Zhang JG et al.Cripto-1and p-STA T3expression in gastric cancer

orming comple with activin and growth actor -ligand and the receptor C -1inhibited activin and --signaling while activin and -are potent inhibitors the gastric mucosa.e speculated that C -1ma pla an important role as a tumorigenic actor and earl gastric tumorigenic molecule during gastric carcinogenesis.n

74eb ru ar 72010olum e 1ssue J w ww.w gn https://www.wendangku.net/doc/593686685.html,

55F y ,|V 6|I 5|

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+++

Gen der

4.052

0.269

Fe male 57

112414880.7Ma le 1214039241866.9

Age (yr) 2.920

0.417

≤61902233231275.6>61

882930151467.0

Borrm ann type 0.1951

Bor Ⅰtype 40301100Bor Ⅱtype 22697072.7Bor Ⅲtype 1404148272470.7Bor Ⅳtype 12434166.7

WH O ’s histological type s <0.0011

P apilla ry.a de.20110100We ll-diff.ade.

9322266.717.872

<0.0012Modera tely-diff.a de.65828111887.7P oorly-d iff.ad e.74272716463.5U ndiff.a de.30120100Mucinou s a de.191133242.1SRC

6213066.7La uren ’s types

28.523<0.001

Intest inal typ e 741129142068.419.566<0.0013

D iffused type 852********.9Mixed type

191133242.1Lymph node m eta stasis 12.3940.006

N o 4923149353.1Yes

129

78.3

Fisher ’s e xa ct test ;2

Well-Mode rate ly-diff.vs Poorly-diff.a de;3

Inte stina l type vs Diffuse d t ype.a de.:A den oc arcinoma s;diff.:Differe ntia ted;S RC:Signet rin g ce ll c arcinoma.

G roups

P -S T A T 3e xpre ssion +→+++(%)χ2P

+++

Gen der 3.091

0.391

Fe male 57

18277568.4Ma le 1215342161056.2

Age (yr) 2.177

0.544

≤6190373513558.9>61

883434101061.4

Borrm ann type 0.9091

Bor Ⅰtype 4120175.0Bor Ⅱtype 221182161.2Bor Ⅲtype 1405553201260.7Bor Ⅳtype 12461166.7

WH O ’s histological type s 0.1001

P apilla ry.a de.20002100We ll-diff.ade.

9440155.6Modera tely-diff.a de.65232310964.5P oorly-d iff.ad e.7435297352.7U ndiff.a de.3120066.7Mucinou s a de.19784063.2SRC 6132083.3

La uren ’s types 11.417

0.076

Intest inal typ e 74272691263.5D iffused type 853********.5Mixed type

19784063.2

Lymph node m eta stasis 9.632

0.021N o 4928163242.9Y 3

66F ’x Zh ang JGet al.Cripto-1and p-STA T3expression in gastric cancer

7eb ru ar 72010olum e 1ssue J w ww.w gn https://www.wendangku.net/doc/593686685.html, es

129

420

1.7

isher s e a ct te st.

IM,the positiv e rates of CR-1was significantly hig her than in normal gastric mucosa (P <0.05),and in GC of the intestinal ty pe was significantly higher than that in the diffused ty pe (P <0.001),indicating that CR-1may be involved in the occurrence of intestinal ty pe of GC.The expression of CR-1in the w ell-to-moderately differ-entiated cancer group w as hig her than in the poorly dif-ferentiated cancer group (P <0.001),which show ed that CR-1expression was correlated with differentiation of GC.M oreov er,our results showed a positiv e correlation between CR-1expression and lymph node metastasis,in GC with lymph node metastasis,the positive rates of CR-1was significantly hig her than that without metas-tasis (P <0.05),which was consistent with the reported findings [16],indicating that CR-1may participate in the development and ly mph node metastasis of G C.CR-1can act as a prog nostic indicator for GC patients.

STAT3maps to human chromosome 2q13-14.1and encodes 750-795amino acids protein.STAT3protein contains six basic domains:an N-terminal conserv ed se-quence,a helix domain,a DNA binding domain,a joining region,a Src homology 2domain (SH2)and a transcrip-tion activation domain.The SH2domain,being most conserved reg ion in STA T3,acts as the cardinal part in STAT3function by participating in tyrosin phosphory la-tion.STAT3is mainly located in the cy toplasm when the cells are in resting state.Upon induction (activation)of ty rosine phosphory lation by a wide variety of cy tokines or growth factors,S TA T3is activated and forms p-STAT3.p-STAT3dimerizes and translocates to the nucleus,fur-ther regulating transcription of target genes [17,18].Many reports have shown that p-STA T3is abnormally activated in most malignant tumors,including squamous cell car-cinoma of the head and neck,breast and GCs [7,19,20].Lee e t al [20]detected p-STAT3expression in 307cases of GC,correlative analy ses between p-STAT3and clinical param-eters demonstrated a positiv e correlation with prognosis of patients with GC.In this study ,we found that the ex -pression of p-STAT3in CAG,IM ,DYSand GC was sig -ni cantly higher than that in normal gastric mucosa (P <0.05),but there was no sig ni cant difference in p-STA T3expression between DYS and GC,suggesting that DYS of gastric mucosa with p-STAT3abnormal activation has y ,ST T3y y f T ST T3x ,

age,Borr mann ’s ty pes,histological types or Lauren ’s ty pes,but p-STA T3expression was sig ni cantly higher in GC w ith ly mph node metastasis than without metastasis (P <0.05),which suggested that the level of p-STAT3expression may indicate the potential for lymph node metastasis and facilitate the prognostic judgment of GC.CR-1can induce activ ation of the cytoplasmic ty rosine k inase c-Src through speci cally binding to Gly pican-1[21],and also can indirectly interact with epidermal growth factor receptor (EGFR)to promote cell survival and proliferation [22];S TA T3can be activated by both EGFR and c-Src [23-25].Based on the previous ndings mentioned above and the results in our study that there is a signi cant association between CR-1expression and p-STAT3activation in GC (r k =0.189,P =0.002),we presume that S TA T3may be the downstream molecule of CR-1,and ov er-expressed CR-1protein participated in occurrence and development of GC through activating STAT3signaling pathway .The relevant molecular mechanism requires further investigations.

In conclusion,CR-1and p-STAT3may take part in the occurrence,dev elopment and metastasis of G C,which can provide theoretical foundation for early diagnosis and judging the prognosis of G C.We discovered that the CR-1expression in G C was positively related to p-STA T3expression.These nding s provide new insights into understanding the molecular mechanism involved in g astric carcinogenesis and progression,and maylead to the development of new approaches for early detection and effective therapy .How ev er,whether CR-1and p-S TA T3collaborate to contribute to gastric carcinogenesis and dev elopment need further studies.

C OMM ENTS Background

Gastri c cancer (GC)i s on e o f th e m al ig nant di seases wi th hi ghest inci dence and m ortali ty rates an d i t is of great sig ni cance to i nv esti gate th e mechan ism s b eh in d th e occurren ce an d d ev el opm en t ofGC.Th e ov er-exp ressio n ofCrip to-1(CR-1)and pho spho ry lati on STA T3(p-ST A T3)has been shown to pl ay an i mpo rtant rol e i n th e tu morigenesis an d cancer prog ression.Therefore,the expl oration in to the correl ation and signi ficance of the exp ressi on of CR-1and p -ST A T3in GC an d precancerou s l esio ns m ay sh ed s a new li ght o n earl y d etectio n and therapy o f GC.

Research frontiers

C R-1and p-ST A T3h ave been shown to exert oncogen ic eff ects i n v ario us h uman n eopl asms.In thi s stu dy ,t he autho rs i nv esti gated th e exp ression of C R-1and p-ST A T3protei ns in atroph ic gastriti s,normal mu cosa,intesti nal m etaplasi a (IM )and GC t o exp lo re i ts correlation w ith gastri c carci nog enesi s and metastasis.Th ey fo und that o ver-ex pression of CR-1and p -STA T3may t ak e p art i n early carcin ogenesi s and metastasi s of GC.

I nnov ations and breakthroughs

CR-1and ST A T3are over-expressed i n a wi de range of human cancers su ch as gastri c,col orectal an d breast carcino mas,an d may pl ay a key rol e in can cer pathog enesi s.Over-ex pressio n o f C R-1and ST A T3increases can cer cel l prol iferatio n,mi grati on,in vasi on and angi ogenesis.Thi s is t he rst stud y to report th at the expression of CR-1and p-STA T3in GC was posi tivel y co rrelat ed,and specu late that there mi gh t be a fu ncti onal rel ati onsh ip b etween C R-1and ST A T3,w here ST A T3mi ghtbe a th e do wnstreammol ecul e o f CR -1.

A pplications

T f R ST T3x y ,IM ,y G x f R ST T356F y ,|V 6|I 5|

W G |j Cripto-1expressi on

p-ST A T3expressi on T otal

-++++++-24216051+28229463++13173538+++695626Tota l

178r k =0.189,P =0.002.

Zhang JG et al.Cripto-1and p-STA T3expression in gastric cancer

a canceration tendenc and p-A ma be involved in the earl events o gastric carcinogenesis.here was no relation bet ween p-A e pression and gender h e positi v e rates o C -1an d p-A e p ressi on were sign i cantl hi gher i n chroni c atro phi c gastri tis d spl asia an d C th an that i n norm al gastri c m ucosa.A nd th e e pression rates o C -1and p-A protein was al so

7eb ru ar 72010olum e 1ssue J w ww.w gn https://www.wendangku.net/doc/593686685.html,

sig nifi cantly h igh er in GC with ly mp h no de metastasi s when compared w ith t hose wi tho ut metastasi s.D etecti on o f C R-1and p-ST A T3protein exp ressi on s m ig ht be help ful i n earl y det ectio n and pro gno si s j udg men t o f GC p ati ents.In addi ti on,CR-1and p-STA T3may serv e as a p otenti altherapeuti c t arget for GC. T erminology

H um an C R-1,al so kn ow n as terato carci n om a-deriv ed gro wth f acto r-1(T DGF-1), i s a m ember of the epidermal growth factor-Cripto-FRL1-Cryptic famil y i nclud ing m ouse C R-1,crypt ic X enop us FRL-1,zebrafi sh one-eyed pi nhead and ch ick Crip to.CR-1functi ons as an on co gene i nv olv ed i n i n vi tro cel lu lar t ransfo rmatio n an d en han cem en t o f cancer cel l pro li ferati on,m i grat io n,i nv asi on and angi og en esi s.STA T3belo ngs to th e STA T fami ly of si gnal transdu cers and activ ators o f transcrip ti on,wh ich pl ay a crit ical ro le i n m ed iati ng cel lu lar resp onses t o v ari ou s sti mu li,m ai n ly fro mtho se o f g rowt h f actors and cy tok i nes.

Peer review

In thi s study,Zhan g et al i nv est igat ed the exp ressio n o f CR-1and p-STA T3 p ro tein s in no rm al m ucosa,I M and GC to expl ore its correl atio n with gastri c carcin og enesi s and metastasi s.I n general,th is i s an i nteresti ng st udy wi th n ew p recisio n o n k no wn m ark ers for GCprog ressi on.

R EFE RE NCES

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浅谈“五四新文化运动的意义”

浅谈“五四新文化运动的历史意义” 通过从中国近代史纲要这本书，我了解到五四新文化运动在中国近代历史上起着重要的作用，同时也是推进中国革命新阶段的必要条件。从当时那些中国先进分子的爱国热情和团结的力量中体会深刻。 1915年9月，新文化运动由陈独秀在上海创办《亲年杂志》（后改名《新青年》领导开始。新文化运动是沿着两条战线展开的，一条是思想战线，一条是文学战线。两条战线交织进行，因而它既是一场思想革命，又是一场文学革命。作为思想革命，它倡导民主和科学，反对专制和愚昧、迷信，提倡新道德，反对旧道德。作为文学革命，它倡导新文学，反对旧文学。它在政治和思想上给封建专制主义及其伦理道德一次沉重的打击，大力宣传了民主和科学，促进了知识青年的觉醒，是新的历史条件下的思想大解放，促使人们更迫切的追求救国救民的真理，为马克思主义在中国的传播创造了条件，也为各种各样外国的哲学、社会科学、自然科学和思想流派的传播敞开了大门。 1919年5月5日，以北大学生为代表，因为不满“巴黎和会”把德国在山东的特权转让给日本，发起了一系列的爱国运动——五四运动。但在五四以前的新文化运动，有着重大的历史意义：新文化运动的倡导者提倡民主、反对专制、提倡科学、反对迷信盲从、是切中时弊的。新文化运动只是开了探求“新文化”的序幕，而五四运动是对新文化运动的一种延续和发展，突出表现在爱国方面。随着时间的变化，人们对五四运动和新文化运动的历史意义的解释越来越走样，把“科学”、“民主”、“爱国”当成这场运动的历史意义。在

那时，新文化运动是生动活泼的，前进的，革命的，并且产生着影响：动摇了封建思想的统治地位；民主和科学思想得到弘扬；为五四运动的爆发作了思想准备。五四运动是一次伟大的爱国运动，也是一次新的文化运动。五四新文化运动发生至如今，虽然已经过了八十年，还仍然是众说纷纭，评价各不相同，观点相去甚远，需要继续探讨。五四新文化运动是对社会现实的回应，是中国近代历史发展的必然，其中马克思主义在中国的广泛传播，并逐渐在思想领域占据主导地位，是五四新文化运动发展到后期的一个显著特征。从五四新文化运动提倡科学与民主，到《新民主主义论》提出“民族的科学的大众的文化”，再到党的十五大提出建设有中国特色社会主义的文化，是一脉相承、不断完善和发展的。五四运动和新文化运动的真正价值，正在于提出了建立中国“新文化”的要求。其中五四运动是中国旧民主主义革命的结束和新民主主义革命的开端，中国革命从此进入了一个新的历史时期，成了中国革命的新阶段即是新民主主义革命阶段的开端并且确定了每年的五月四号是中国青年节。可见，五四运动在中国历史上意义的重大。

脐带干细胞综述

脐带间充质干细胞的研究进展间充质干细胞（mesenchymal stem cells,MSC S ）是来源于发育早期中胚层的一类多能干细胞[1-5]，MSC S 由于它的自我更新和多项分化潜能，而具有巨大的治疗价值 ,日益受到关注。MSC S 有以下特点：(1)多向分化潜能，在适当的诱导条件下可分化为肌细胞[2]、成骨细胞[3、4]、脂肪细胞、神经细胞[9]、肝细胞[6]、心肌细胞[10]和表皮细胞[11, 12]；(2)通过分泌可溶性因子和转分化促进创面愈合；(3) 免疫调控功能，骨髓源（bone marrow ）MSC S 表达MHC-I类分子，不表达MHC-II 类分子，不表达CD80、CD86、CD40等协同刺激分子，体外抑制混合淋巴细胞反应，体内诱导免疫耐受[11, 15]，在预防和治疗移植物抗宿主病、诱导器官移植免疫耐受等领域有较好的应用前景；(4)连续传代培养和冷冻保存后仍具有多向分化潜能，可作为理想的种子细胞用于组织工程和细胞替代治疗。1974年Friedenstein [16] 首先证明了骨髓中存在MSC S ，以后的研究证明MSC S 不仅存在于骨髓中，也存在于其他一些组织与器官的间质中：如外周血[17]，脐血[5]，松质骨[1, 18]，脂肪组织[1]，滑膜[18]和脐带。在所有这些来源中，脐血(umbilical cord blood)和脐带(umbilical cord)是MSC S 最理想的来源，因为它们可以通过非侵入性手段容易获得，并且病毒污染的风险低，还可冷冻保存后行自体移植。然而，脐血MSC的培养成功率不高[19, 23-24]，Shetty 的研究认为只有6%，而脐带MSC的培养成功率可达100%[25]。另外从脐血中分离MSC S ，就浪费了其中的造血干/祖细胞(hematopoietic stem cells/hematopoietic progenitor cells,HSCs/HPCs) [26, 27]，因此，脐带MSC S (umbilical cord mesenchymal stem cells, UC-MSC S )就成为重要来源。一．概述人脐带约40 g, 它的长度约60–65 cm, 足月脐带的平均直径约1.5 cm[28, 29]。脐带被覆着鳞状上皮，叫脐带上皮，是单层或复层结构，这层上皮由羊膜延续过来[30, 31]。脐带的内部是两根动脉和一根静脉，血管之间是粘液样的结缔组织，叫做沃顿胶质，充当血管外膜的功能。脐带中无毛细血管和淋巴系统。沃顿胶质的网状系统是糖蛋白微纤维和胶原纤维。沃顿胶质中最多的葡萄糖胺聚糖是透明质酸，它是包绕在成纤维样细胞和胶原纤维周围的并维持脐带形状的水合凝胶，使脐带免受挤压。沃顿胶质的基质细胞是成纤维样细胞[32]，这种中间丝蛋白表达于间充质来源的细胞如成纤维细胞的，而不表达于平滑肌细胞。共表达波形蛋白和索蛋白提示这些细胞本质上肌纤维母细胞。脐带基质细胞也是一种具有多能干细胞特点的细胞，具有多项分化潜能，其形态和生物学特点与骨髓源性MSC S 相似[5, 20, 21, 38, 46]，但脐带MSC S 更原始，是介于成体干细胞和胚胎干细胞之间的一种干细胞，表达Oct-4, Sox-2和Nanog等多

雅思口语素材汇总之端午节

雅思口语素材汇总之端午节雅思口语素材:Dragon Boat Festival(端午节) Qu Yuan The Dragon Boat Festival, also called the Duanwu Festival, is celebrated on the fifth day of the fifth month according to the Chinese calendar. For thousands of years, the festival has been marked by eating zong zi (glutinous rice(糯米)wrapped to form a pyramid using bamboo or reed leaves) and racing dragon boats. The festival is best known for its dragon-boat races, especially in the southern provinces where there are many rivers and lakes. This regatta(赛舟会)commemorates the death of Qu Yuan , an honest minister who is said to have committed suicide by drowning himself in a river. Qu was a minister of the State of Chu situated in present-day Hunan and Hubei provinces, during the Warring States Period (475-221BC)(战国时期). He was upright, loyal and highly esteemed for his wise counsel that brought peace and prosperity to the state. However, when a dishonest and corrupt prince vilified Qu, he was disgraced and dismissed from office. Realizing that the country was now in the hands of evil and corrupt officials, Qu grabbed a large stone and leapt into the Miluo River on the fifth day of the fifth month. Nearby fishermen rushed over to try and save him but were unable to even recover his body. Thereafter, the state declined and was eventually conquered by the State of Qin. The people of Chu who mourned the death of Qu threw rice into the river to feed his ghost every year on the fifth day of the fifth month. But one year, the spirit of Qu appeared and told the mourners that a huge reptile(爬行动物)in the river had stolen the rice. The spirit then advised them to wrap the rice in silk and bind it with five different-colored threads before tossing it into the river. During the Duanwu Festival, a glutinous rice pudding called zong zi is eaten to symbolize the rice offerings to Qu. Ingredients such as beans, lotus seeds(莲子), chestnuts(栗子), pork fat and the golden yolk of a salted duck egg are often

脐带血造血干细胞库管理办法(试行)

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雅思口语素材 Document serial number【LGGKGB-LGG98YT-LGGT8CB-LGUT-

Useful Expressions: Words and phrases Friends and communication: solidify/ strengthen/ enhance/ promote communication / connection with mutual understanding relationship network/circle of f r i e n d s cultivate/develop friendship with s b . keep steady relationship with sb. establish interpersonal networksac build up the social circle spur message transmission Knowledge and experience widen one’s outlook broaden one’s vision/horizon acquire knowledge and skills comprehensive/overall quality

expand/enlarge one’s scope of knowledge knowledge reserve/base/storage theoretical knowledge practical skills social experience broaden one’s knowledge base promote one’s overall/ comprehensive competence accumulate experiences learn lessons from past experiences Work and experience the scarcity of employment o p p o r t u n i t i lay the foundations for career p r o s p e r i t y

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U s e f u l E x p r e s s i o n s: Words and phrases Friends and communication: mutual understanding solidify/ strengthen/ enhance/ promote communication / connection with relationship network/circle of friends cultivate/develop friendship with sb. keep steady relationship with sb. establish interpersonal networksac build up the social circle spur message transmission Knowledge and experience widen one’s outlook broaden one’s vision/horizon acquire knowledge and skills comprehensive/overall quality expand/enlarge one’s scope of knowledge knowledge reserve/base/storage theoretical knowledge practical skills social experience broaden one’s knowledge base promote one’s overall/ comprehensive accumulate experiences competence learn lessons from past experiences Work and experience the scarcity of employment opportunities lay the foundations for career prosperity immerse oneself in endless job tasks boost/augment/enhance efficiency be adept in boost one’s c ompetitiveness Health and pressure diminish individuals' leisure time drive away lassitude lighten one’s burden homework/workforce overload

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Describe a monument Describe an interesting building Describe a lake, river or sea. Describe a peaceful place Describe a leisure place Describe a park Describe a place of interest Describe a natural beauty Describe a city you want to live in Describe a place you have visited Describe a place you always go for shopping

论五四新文化运动的历史意义

论五四新文化运动的历史意义新文化运动是沿着两条战线展开的，一条是思想战线，一条是文学战线。两条战线交织进行，因而它既是一场思想革命，又是一场文学革命。作为思想革命，它倡导民主和科学，反对专制和愚昧、迷信，提倡新道德，反对旧道德。作为文学革命，它倡导新文学，反对旧文学。前期的新文化运动实质是资产阶级的新文化反对封建旧文化的斗争。后期极力宣传马克思主义。新文化运动的进步性民主和科学思想的弘扬，动摇了封建思想的统治地位，并且推动了中国自然科学的发展，使人们的思想尤其是青年的思想得到空前的解放。后期传播的马克思主义，为中国先进的知识分子所接受，成为拯救国家、改造社会的思想武器。对五四运动的爆发起到了宣传动员作用，也有利于文化的普及和繁荣。新文化运动的局限性新文化运动是由资产阶级激进民主主义者发动的。它有伟大的功劳，也有严重的缺点。运动的倡导者忽视人民群众，没有把新文化运动同广大群众相结合，使文化运动局限在知识分子的圈子里。他们还回避当时对军阀政府的实际斗争，也没有正面提出反帝的任务。以当时的文学革命而论，虽然提出建设“国民文学”，但当时的文学活动也只限于一部分知识分子中，还没有可能普及到工农群众中去。对中国古典文学的一味批判具有片面性。新文化运动的影响

（1）动摇了封建思想的统治地位。新文化运动前，资产阶级改良派和革命派，在宣传各自的政治观点时，都没有彻底地批判封建思想。经过新文化运动，封建思想遭到前所未有的冲击批判，人们的思想得到空前的解放。（2）民主和科学思想得到弘扬。中国知识分子在新文化运动中，受到一次西方民主和科学思想的洗礼。这就为新思潮的传播开辟了道路，也推动了中国自然科学事业的发展。（3）为五四运动的爆发作了思想准备。新文化运动启发了民众的民主主义觉悟，对五四爱国运动起了宣传动员作用。（4）后期传播的社会主义思想，启发了中国先进的知识分子，使他们选择和接受了马克思主义，作为拯救国家、改造社会和推进革命的思想武器。这是新文化运动最重要的成果。（5）有利于文化的普及和繁荣。新文化运动提倡白话文，能够使语言和文字更紧密地统一起来，为广大民众所接受，从而有利于文化的普及与繁荣。不过，新文化运动中的先进分子，大多有一些偏激情绪，对东西方文化的看法，存在着绝对肯定或绝对否定的偏向，这种看法一直影响到后来。其实无论是东方或西方,都应该互相地取长补短,这样才能共同进步.。

Simon考官范文-雅思口语素材2(Cook整理)

一.雅思P2相关话题一日假期和外国朋友一起吃饺子的建议 1.The best way to eat a dumpling is in one bite. “Dumplings are designed to be consumed in one mouthful, as it’s the best way to enjoy the combination of the meat filling and the very thin and springy flour wrapper,” If you can’t use chopsticks, eat your dumplings with your fingers. Avoid using a fork at all costs, as piercing the dumpling will compromise the flavour. 3.Mix two parts vinegar with one part soy sauce for the perfect dumpling sauce. Add young ginger slices too， Chili oil is also a great addition when available. 4.Dumplings are just one element of dim sum. “Dim sum doesn’t just include dumplings. It’s also braised dishes like pork ribs, chicken feet, and beef balls. It’s actually small tapas-style dishes that are eaten in Cantonese restaurants at lunchtime,” 5.Xiao long bao dumplings are different from others as they contain broth. They originated in the Jiangnan region of China and are prepared in bamboo steaming baskets called xiao long, hence the name. 6.When eating xiao long bao or a dumpling with a ~soupy~ interior, opt for chopsticks and a spoon. “As soon as the dumplings arrive at your table, lift one from the steamer basket onto a soup spoon. Next, tear the skin of the dumpling by pressing the chopsticks from the side of the dumpling onto the spoon. The broth will ooze out onto the spoon. Sip the soup then enjoy the dumpling in one mouthful.” 7.You can tell whether your dumpling was cooked fresh or frozen by looking at the skin. “The skin of a freshly made dumpling is springy and light. “Frozen ones tend to be soggy.” 8.When makingdumplingsat home, try to keep your packages small.

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