Smad2 and Smad6 as predictors of overall survival in oral squamous cell carcinoma patients.
BACKGROUND
To test if the expression of Smad1-8 mRNAs were predictive of survival in patients with oral squamous cell carcinoma (SCC).


METHODS
We analyzed, prospectively, the expression of Smad1-8, by means of Ribonuclease Protection Assay in 48 primary, operable, oral SCC. In addition, 21 larynx, 10 oropharynx and 4 hypopharynx SCC and 65 matched adjacent mucosa, available for study, were also included. For survival analysis, patients were categorized as positive or negative for each Smad, according to median mRNA expression. We also performed real-time quantitative PCR (QRTPCR) to asses the pattern of TGFbeta1, TGFbeta2, TGFbeta3 in oral SCC.


RESULTS
Our results showed that Smad2 and Smad6 mRNA expression were both associated with survival in Oral SCC patients. Cox Multivariate analysis revealed that Smad6 positivity and Smad2 negativity were both predictive of good prognosis for oral SCC patients, independent of lymph nodal status (P = 0.003 and P = 0.029, respectively). In addition, simultaneously Smad2- and Smad6+ oral SCC group of patients did not reach median overall survival (mOS) whereas the mOS of Smad2+/Smad6- subgroup was 11.6 months (P = 0.004, univariate analysis). Regarding to TGFbeta isoforms, we found that Smad2 mRNA and TGFbeta1 mRNA were inversely correlated (p = 0.05, R = -0.33), and that seven of the eight TGFbeta1+ patients were Smad2-. In larynx SCC, Smad7- patients did not reach mOS whereas mOS of Smad7+ patients were only 7.0 months (P = 0.04). No other correlations were found among Smad expression, clinico-pathological characteristics and survival in oral, larynx, hypopharynx, oropharynx or the entire head and neck SCC population.


CONCLUSIONS
Smad6 together with Smad2 may be prognostic factors, independent of nodal status in oral SCC after curative resection. The underlying mechanism which involves aberrant TGFbeta signaling should be better clarified in the future.
Mangone
Flavia R R
FR
Disciplina de Oncologia, Departamento de Radiologia, LIM 24, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Avenida Dr Arnaldo 455, São Paulo, Brasil. flavia@lim24.fm.usp.br
Walder
Fernando
F
Maistro
Simone
S
Pasini
Fátima S
FS
Lehn
Carlos N
CN
Carvalho
Marcos B
MB
Brentani
M Mitzi
MM
Snitcovsky
Igor
I
Federico
Miriam H H
MH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000096:biosynthesis* / Q000235:genetics; D051905:Smad6 Protein / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000235:genetics; D053782:Transforming Growth Factor beta3 / Q000096:biosynthesis / Q000235:genetics
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C497782:SMAD2 protein, human; C497802:SMAD6 protein, human; D051899:Smad2 Protein; D051905:Smad6 Protein; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3
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