title: The prognostic significance of Smad3, Smad4, Smad3 phosphoisoform expression in esophageal squamous cell carcinoma.
abstract: Smad3 functions as an integrator of diverse signaling, including transforming growth factor β signaling and the function of Smad3 is complexly regulated by differential phosphorylation at various sites of Smad3. Despite the importance of Smad3 and its various phosphoisoforms, their prognostic significance has rarely been studied. In this study, we demonstrated the prognostic significance of Smad3, its phosphoisoforms, and Smad4 expression by immunohistochemistry in 126 esophageal squamous cell carcinomas. The phosphoisoforms of Smad3 studied in this article included phosphorylation at C-terminal (pSmad3C)(Ser(423/425)) and phosphorylation at the linker region (pSmad3L)(Ser(213)). High expression of Smad3 was associated with shorter overall survival. Co-existence of high expression of pSmad3L(S213) and low expression of pSmad3C(S423/425) were associated with advanced N stage and an independent prognostic factor for overall [hazard ratio (HR) 2.03, 95 % confidence interval (CI) (1.10-3.75), p = 0.023] and disease-free survival [HR 2.41, 95 % CI (1.32-4.39), p = 0.004]. In conclusion, co-existence of high pSmad3L(Ser(213)) expression and low pSmad3C(Ser(423/425)) expression can be considered as immunohistochemical biomarkers for predicting prognosis as well as future therapeutic targets. In addition, our results of combinatory effect of differential phosphorylation of Smad3 on prognosis suggest the mode of action of Smad3 might be logically determined by its phosphorylation pattern.
authors.affiliation: Department of Pathology and Translational Genomics, Samsung Medical Center, School of Medicine, Sungkyunkwan University, 50 Ilwon-dong, Gangnam-gu, Seoul, 135-710, Korea.
authors.forename: Soo Youn
authors.initials: SY
authors.lastname: Cho
authors.forename: Sang Yun
authors.initials: SY
authors.lastname: Ha
authors.forename: Song-Mei
authors.initials: SM
authors.lastname: Huang
authors.forename: Jeong Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Myung Soo
authors.initials: MS
authors.lastname: Kang
authors.forename: Hae-Yong
authors.initials: HY
authors.lastname: Yoo
authors.forename: Hyeon-ho
authors.initials: HH
authors.lastname: Kim
authors.forename: Cheol-Keun
authors.initials: CK
authors.lastname: Park
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Um
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D004938:Esophageal Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020033:Protein Isoforms / Q000096:biosynthesis; D051900:Smad3 Protein / Q000096:biosynthesis*; D051901:Smad4 Protein / Q000096:biosynthesis*; D015996:Survival Rate / Q000639:trends
chemical_list: D014408:Biomarkers, Tumor; D020033:Protein Isoforms; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; D051901:Smad4 Protein