Copyright© ABE&M todos os direitos reservados. original article original São Paulo, SP, Brazil de CabeçaePescoço, USP, Católica (PUC),Sorocaba,SP, Brazil Patologia, Pontifícia Universidade 406 Accepted onFeb/24/2010 Received onNov/7/2009 [email protected] 05508-000 − São Paulo, SP, Brazil Av. Prof. Lineu Prestes, 1524 Universidade de São Paulo Instituto de Ciências Biomédicas, e do Desenvolvimento, Departamento de Biologia Celular Edna T. Kimura Correspondence to: 3 2 1 USP), SãoPaulo, SP, Brazil Universidade deSãoPaulo (ICB- Instituto deCiênciasBiomédicas, Celular edoDesenvolvimento, Departamento deBiologia Departamento Departamento deCirurgiaDepartamento deMorfologiaDepartamento e atenuação expressão Although transduction no express SMAD7 a was observed by Phosphorylated expression signalinginthyroidSMADs antiproliferative carcinomas. Celso U. M. Celso Friguglietti Metab. 2010;54(4):406-12 da Objective: ABS SMAD2/3; SMAD4; SMAD7; câncer de tiroide; TGF- tiroide; de câncer SMAD7; SMAD4; SMAD2/3; Descritores mediators, inhuman thyroid tissues TGF-beta/activin signaling Expression ofSMADproteins, Objetivo: R TGF- cancer; thyroid SMAD7; SMAD4; SMAD2/3; Keywords E. Matsuo Sílvia humana tiroide de tecidos de em TGF-beta/activina, SMAD, sinalização da proteínas de mediadores Expressão proteica câncer. was of of e observada e lar. the pSMAD2/3 missão tumores
folicular ESUMO inativação SMAD7
the tumor
expressão núcleo immunohistochemistry. Embora inactivation not evaluated TR inhibitory
do SMAD AC
high
exhibited de different de TGF-b
cells
Investigar
por exibissem
de
in
de sinal da
tanto To não T
SMADs in TGF-
tiroide dos
levels
both células generated
de imuno-histoquímica. SMAD7 thyroid sinalização
investigate indicates
2 in foi
and
gerado
SMAD b of SMAD7, SMADs em e componentes
between
multinodular
e
high 1 diferente benign SMAD3 TGF- b/activin
expressam , Ana Paula Z. ,P. Paula Ana Fiore
of
foi
activina
activin
a tumorais tumores alta
these cells
expressão inibitório, avaliada
2 cytoplasmic por by
propagation em mostly
and positividade antiproliferativa 1 the
and TGF-b and benign Results: , Maria C. ,Ferro Maria
exert fosforilados
proteins.
TGF- entre exerçam células
SMAD3
benignos
indicam
altos expression
da em the malignant
goiter, in
principalmente b signaling antiproliferative de
and
lesões
sinalização Resultados:
e and malignant bócio
presence
níveis tiroidianas activina, proteínas staining Materials and methods:
The
(pSMAD2/3) efeitos b of activin,
citoplasmática propagação ; activin ;
follicular malignant b como (pSMAD2/3) TGF- b/activin
,activina benignas multinodular,
expression de dessas of thyroid components 1
antiproliferativos , Simone M. ,Siguematu Simone of in
2 enquanto
SMADs tumors, while
SMAD de malignos , A.Marco V.Kulcsar SMAD
e A
pSMAD2/3 carcinomas,
em
TGF- adenoma,
a
expressão roles proteínas.
lesions. associated
e presença da tumors.
SMAD7
tumores malignas
associados
em proteins b
em em sinalização of signaling. could
/activina
adenoma in
SMAD7 da is
pSMAD2/3, carcinomas, thyroid tecidos carcinomas Arq Bras Endocrinol Metab. 2010;54(4):406-12
Conclusions: reported and tiroide.
papillary
Although de contribute inhibits das Materiaisemétodos:
the malignos, with
The
da nas
Arq Bras Metab. Endocrinol 2010;54/4 in
pSMAD2/3,
é SMAD4 inibe
proteínas
com
However, nuclear
folicular,
TGF- tiroide. follicular relatada de human protein
the
células Embora
in this tiroide
SMAD4 essa and b SMAD4 a de SMAD4 1,3 pSMAD2/3, /activina. several
to
positividade poderia proteins , T.Edna Kimura
1 The intracellular Conclusões: staining tiroide.
,N. Ebina Kátia
expression the thyroid
carcinomas
follicular em foliculares
sinalização pSMAD2/3 cells, SMAD4
the
pSMAD2/3, humana finding
attenuation and diversos induce induzem high types
Contudo, thyroid contribuir ArqBrasEndocrinol in of tissues
SMAD7 SMAD4 A e the carcinomas
expression
pSMAD2/3
SMAD7 nuclear desde of expressão da of
of signaling. the papilífero e O intracelu
tipos nucleus
a SMAD4
SMAD4 SMADs SMADs tumors achado cancer. tiroide,
signal
of trans a
since
para 1
was and que 1 alta the
,
foi de de - - teins in thyroid tumors. teins inthyroid - pro SMAD7 and SMAD4 SMAD2/3, of expression the analyzing by signaling TGF- b/activin of integrity the investigated we study, this in Therefore, (17,22). cancers epithelial several of progression and lopment deve- the in identified been has transduction signal of impairment An (20,21). B activin and A activin forms, iso- activin as well as TGF b-3 and TGFb-2 TGFb-1, isoforms, TGF-b the express tumors thyroid that ted repor previously have we cells, follicular thyroid mal nor of proliferation the on effects inhibitory exert vin follicular cells (13-19). Although both TGF-b and acti- thyroid including cells prostatic and pancreatic mary, tors for epithelial cells, such as hepatic, intestinal, mam- (11,12). SMAD4 and SMAD2/3 plex com of formation the with of interferes and SMAD2/3 phosphorylation prevents that (I-SMAD) SMAD inhibitory an SMAD7, by attenuated is signaling vin TGF- This (6-10). recruited transduction is signal its SMADs for of set same the receptors, cific spe own its to binds activin Although transcription. this gene then regulates it where nucleus the to moves and complex SMAD4, (co-SMAD), SMAD common-me diator with interaction SMAD2/ their of allows SMAD3 activation The SMAD3. and (R-SMAD), SMAD2 SMADs receptor-regulated the activate TGF- to complexed The receptors proteins. SMAD by mediated signaling cellular intra induce which receptors, transmembrane kinase (4,5). development TGF- and apoptosis differentiation, and proliferation cell regulating processes, biological of variety wide a affect which proteins morphogenetic TGF- the including proteins yet not clarified (2,3). mechanism a by pathway, inhibitory activin TGF-b/ of unbalance the including signaling, cellular intra- several of disruption a in result that alterations molecular on dependent is transformation malignant thyroid The (1). carcinoma) (anaplastic differentiated poorly and carcinomas) follicular and (papillary tiated - differen as allocated are which tumors, malignant and goiters) multinodular and (adenomas tumors benign Arq Bras Metab. Endocrinol 2010;54/4 T Introduction and activin are proliferation-inhibitory fac- proliferation-inhibitory are activin and TGF-b TGF- The of the endocrine system (1). They are classified as classified are They (1). system endocrine the of neoplasms common most the are tumors hyroid b acts by binding to specific serine/threonine serine/threonine specific to binding by acts b superfamily is comprised of related related of comprised is superfamily b b s, activins and bone bone and activins s, phosphorylate and and phosphorylate b /acti ------
in S) n wr sbitd o nlss f variance of analysis to submitted were and (SD) tion mean the as presented are data The staining. immunohistochemical of results quantitative peptides (antibody/peptide: 1/5) overnight. logy) and SMAD7 (sc-7004 P, Santa Cruz p tide,Biotechnology) antibody primary preabsorbed with corresponding pep primary antibody (SMAD4) and incubating tissues with pS- MAD2/3 wasalsodetermined. for cells stained nuclear of percentage The cells. 900 of total a in tissue the in chosen randomly areas 3 counting by determined was cells immunopositive pSMAD2/3 of percentage The cells. positive of 50% than more in present intensity staining the considered we tissue, same the in even seen positivity of intensity classified as weak, moderate and strong. Due to variable and evaluated was cells follicular of immunostaining of intensity The microscopy. light by observed staining brown as detected was reaction the of munopositivity im- The hematoxylin. Gill’s with counterstained then were sections The peroxide. hydrogen with benzidine the reaction was revealed by a mixture of 3,3’-diamino- biotin-streptavidin-peroxidase, with incubation After PBS. in washed were tissues the incubation antibodies the Between albumin. 0.05% and saline Tris-buffered in 1:100 at diluted were antibodies primary The night. over Biotechnology) Cruz Santa (sc-7004, antibody anti-SMAD7 polyclonal goat or Biotechnology) Cruz Cruz, Santa (sc-7154, anti-SMAD4 polyclonal rabbit Santa or CA) Biotechnology, Cruz Santa (sc-11769, antibody SMAD2/3 anti-phosphorylated polyclonal goat with incubated were and (PBS) saline te-buffered roxide for 15 minutes, tissues were washed in phospha- pe- hydrogen 3% with blocked was endogenous activity peroxidase after Briefly, (23). previously as described method immunoenzymatic 3-stage indirect an by performed was procedure immunohistochemical The concentrations. alcohol decreasing of series a through hydration and xylene in deparaffinization to submitted were 9), = n (PC, carcinoma carcinoma papillary and 4) = follicular n (FC, 5), = n (FA, adenoma follicular 10), = n (MNG, goiter multinodular 12), = n (N, sue tissuebyimmunohistochemicalmethod. thyroid tumoral and normal in SMAD7, and SMAD2/3 ted - phosphoryla SMAD4, of expression the analyzed We Ma h saitcl nlss a md uig h semi- the using made was analysis statistical The the omitting performed was control negative The sections human from oftis- thyroid normal Paraffin terials andmethos SMAD2/3 (sc-11769 P, Santa Cruz BiotechnoP,(sc-11769SMAD2/3 Cruz Santa SMADs expression inhuman thyroid standard devia- standard ± 407 - -
Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. Intensity: negative(-),weak (+),moderate(++),strong(+++). Table 1. ImmunohistochemicalanalysisofSMAD4,pSMAD2/3andSMAD7 SMADs expression inhuman thyroid 408 nuclear positivity of SMAD4 in detected both benign and malig- also We 2B). (Figure tissues carcinoma and tivity was about 30% and was similar in MNG, adenoma posi- pSMAD2/3, of staining nuclear the analyzed we (P tissues MNG in than adenomas and carcinomas in abundant more were cells munopositive Im- 2B). (Figure tissue normal with compared when tive cells for pSMAD2/3 was higher in tumoral samples posi- of number the that showed expression MAD2/3 pS- of analysis immunohistochemical The 2A). (Figure tissues tumor thyroid in level subcellular the at protein this of localization the and cells positive pSMAD2/3 of percentage the evaluated we tumors, thyroid in ling tissues issummarizedintable1. neoplastic and normal the in staining nohistochemical immu- of analysis The 1). (Figure papillary) and cular (folli- carcinomas in stronger is expression its however tissues, all in detected was SMAD2/3 Phosphorylated cells. negative and positive displaying follicle given with a tissue same the in observed was SMADs of vity positi- heterogeneous MNG, In strong. and geneous homo- predominantly neoplastic was carcinoma papillary the of cells in SMADs of pattern expression The Resul tute, UniversityofSaoPaulo,Brazil. Insti - Sciences Biomedical the of Research Human for significantatP<0.05. red - conside were Differences samples. between results re followed by the Student Newman-Keuls test to compa- FA (n=5) FC (n=4) MNG (n=10) PC (n=9) Normal (n=12) To investigate the integrity of SMAD signa- further Committee Ethical the by approved was study This ts % % % % % N N N N N 40 25 20 75
2 1 2 9 - 40 80 33 25 + 2 8 3 3 SMAD4 < 0.05). When 0.05). < ++ 20 22
1 2 +++ 45 75 4 3 was predominantly cytoplasmic. was predominantly SMAD7 of immunostaining the whereas lesions, nant whereas these proteins are rarely detected in normal normal thyroid tissue. SMAD in proteins mediate antiproliferative detected rarely are proteins these whereas lesions, malignant to benign from thyroid of stages ral SMAD7 are expressed in well all as of inhibitory tumo- as pSMAD2/3 and SMAD4 2, figure in illustrated As tumors. thyroid in SMAD7 and pSMAD2/3 SMAD4, of expression the investigated pathway,we SMAD of the integrity the verify to study, present the In (6-8). pathway this for SMAD inhibitory an is SMAD7 while pathway,signaling this of SMADs stimulatory the ting - represen mediators, intracellular TGF-b/activin are SMAD4 and SMAD3 SMAD2, (27). pathway Smad functional a by by mediated possibly activin, and TGF-b1 distinctly generated effect antiproliferative the to sensitive still is line cell carcinoma thyroid papillary a that shown have Conversely,we TGF-b. to responsive ir became lesions benign from derived cells even that proving (26), TGF-b of presence the in inhibited not was proliferation samples, goiter human In (2). cancer TGF-b/activin responsiveness is frequently in observed of loss cells, neoplastic in proteins these of expression increased the Despite (20,21). negative predominantly is tissue normal in expression the cancer,while thyroid in expression protein activin and TGF-b high shown previously have we Similarly, (17,19,25). carcinomas several in overexpressed are activin and TGF-b wever, Ho- (24). cells thyroid follicular including cells, thelial epi- in effects antiproliferative exert activin and TGF-b Discussion 25 3 - 40 60 75 pSMAD2/3 + 2 6 9 ++ 20 11 25 2 1 1 +++ 60 20 89 75 3 2 8 3 Arq Bras Metab. Endocrinol 2010;54/4 20 58 1 7 - 60 80 22 25 + 3 8 2 3 SMAD7 ++ 20 45 17 25 2 4 2 1 +++ 20 33 75 1 3 3 - Arq Bras Metab. Endocrinol 2010;54/4 papillary adenoma, follicular (MNG), goiter multinodular tissue, normal carcinoma andfollicular carcinoma.Nucleiwerecounterstained withhematoxylin, which appear inblue.Bar=50mm. from sections representative in staining brown by shown is immunoreaction 1. Figure carcinoma carcinoma Follicular Follicular Papillary adenona MNG Normal Immunohistochemical staining for pSMAD2/3, SMAD4 and SMAD7 in human thyroid tumors by the peroxidase method. The positivity of positivity The method. peroxidase the by tumors thyroid human in SMAD7 and SMAD4 pSMAD2/3, for staining Immunohistochemical
pSMAD2/3 SMAD4 SMADs expression inhuman thyroid SMAD7 409
Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 410 of thecascadesuchasSMADs. plex is intact and able to activate downstream mediators com- activin/receptor or TGF-b/receptor the that tes of pSMAD2/3 in the nucleus of neoplastic cells indica- among tumors not (Figure different 2B). The presence of nuclear positive cells for pSMAD2/3 was expression 2B) percentage (Figure the (MNG), lesion benign carcinomas in with compared higher significantly was for theSMADspathway(2,31,32). role suppressive tumor potential a conferring cancers, tified in the development and progression of a variety of TGF-b or activin receptors and SMADs, has been iden- either in mutations or deletions as such components, veness caused by inactivation of the signaling pathway’s - responsi TGF-b/activin of loss The (22,28-30). tivin in several epithelial cell lines responsive to TGF-b or ac- tors, p15 and p21, and by inhibiting c-MYC expression inhibi- CDK the of expression the inducing by effects FC (n=4)andPC9).*P<0.05vs.normal.Blackbarsinthegraphrepresent percentageofnuclearpositivecells. quantitative analysis of pSMAD2/3 immunopositivity. The graph shows the percentage of positive cells inis normal tissuecells (N, follicular n = 12), of MNG (n shown = positivity 10),by brown FAstaining. The nuclear sections (nwere =counterstained 5),with and hematoxylin and negative cytoplasmic nuclei for pSMAD2/3 were The stained blue. Bar = (PC). 25 carcinoma papillary (FC), carcinoma follicular (FA), adenoma follicular (MNG), goiter Figure 2. B A SMADs expression inhuman thyroid Although the number of pSMAD2/3 positive cells positive pSMAD2/3 of number the Although Immunohistochemical analysis of pSMAD2/3 expression in thyroid tumors. (A) Immunohistochemical localization of pSMAD2/3 in multinodular
% positive cells 100 150 MNG 50 0 N FA MNG * pSMAD2/3 duction (37). Up-regulation of SMAD7 is reported in reported is SMAD7 of Up-regulation (37). duction upon TGF-b/receptor activation to inhibit signal trans- cytoplasm the in accumulates SMAD7 stimulus, ligand upon induced translocation nuclear display SMAD4, and SMAD3 SMAD2, Unlike (36). signaling activin representing a negative feedback mechanism of TGF- activin or TGF-b either by induced is SMAD7 of tion transcrip- The (34,35). activin and TGF-b by induced in thecarcinomas. most thyroid tumors, displaying high expression mainly in our study,lon carcinomas, in SMAD4 was expressed from what Differently in is pancreatic observed and co- recently, in thyroid tumors, were also reported (28,33). more and, carcinomas colon as such cancers others in gene this of deletions or mutations Inactivating noma. in the gene encoding deletions of frequency high to due 4) locus carcinoma FA * MD ihbt te rwh ret n apoptosis and arrest growth the inhibits SMAD7 pancreatic in (deleted DPC4 as known is SMAD4 FC FC * SMAD4 found in pancreatic - carci Arq Bras Metab. Endocrinol 2010;54/4 PC * PC mm. (B) Semi- b / Arq Bras Metab. Endocrinol 2010;54/4 DeLellis 1. References was reported. Disclosure: no potential conflict of interestrelevant to this article grants to SMS. ETK is a CNPq-funded investigator.fellowship CNPq and APZPF to grants fellowship Capes KNE, to and APZPF SEM, fellowshipFapesp togrants by and (CNPq) ment pes)andNational Counsel Technologicalof andScientific Develop ordinationImprovementtheHigherforEducation of Personnel (Ca ResearchFoundation(Fapesp),StateCo Paulo Sao the fromgrants tical review of the manuscript. This study was supported by research Acknowledgments: w carcinomas. mostlyinthyroid served ob- SMAD7, SMAD, antagonist an of expression high the by attenuated be could proteins TGF-b/activin by induced signal SMADs antiproliferative the However, progression. tumor limit to critical is signaling rative - antiprolife This tumors. thyroid in intact is pathway signaling TGF-b/activin the that indicates MAD2/3 pS- and SMAD4 SMADs, stimulatory the for sitivity tumorigenesis. involved inthyroid also be may SMAD7 that indicating carcinomas, cular folli- and papillary in SMAD7 inhibitory of expression increased detected we tumor, thyroid In (38-40). sion - progres cancer in implicated is and carcinomas several . Derynck 2. . Massague 3. . Derynck 4. Moustakas 5. . ten 7. . Pangas 6. . Shi 9. Mehra 8. 1 Hayashi 11. 0 Kimura 10. 2 Lebrun 12. n hs td, h peec o ncer immunopo- nuclear of presence the study, this In Lyon: IARCPress; 2004. ppression trol, cancer, Cell.2000;103(2):295-309. andheritabledisorders. mours. phys Trends EndocrinolMetab.2000;11(8):309-14. TGF-beta signaltransduction.JCellSci. 2001;114(Pt 24):4359-69. on pathway. Biochem CellBiol.2002;80(5):605-22. 2000;25(2):64-70. 2007;51(5):683-9. SMAD membrane tothenucleus.Cell.2003;113(6):685-700. tor MAD-related 1997;89(7):1165-73. and nol. 1999;13(1):15-23. nuclear Y, and Dijke inhibitory Acta. 1997;1333(2):F105-50. Massague signalling A, pathology
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Wrana P, and
Akhurst J, Abdollah Takabe A, effectors Feng Matsuo Woodruff Miyazono Lloyd Blain protein
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