title: Phosphatase PPM1A is a novel prognostic marker in pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) harbors complex molecular alterations and remains a lethal disease. Aberrant TGF-β/Smads signaling is a well-known mechanism involved in the progression of PDACs. However, loss of Smad4 expression is reported in only ~50% of PDACs and is generally associated with worse prognosis. Investigating additional prognostic markers is warranted. PPM1A is a phosphatase that dephosphorylates TGF-β-activated Smad2/3 and inactivates the TGF-β signaling. Little is known about the clinical significance of PPM1A in PDACs and its functional relationship to Smad4. In this study, PPM1A and Smad4 immunohistochemistry was assessed in 180 R0 resected human PDACs. PPM1A was lost in 41.7% cases, whereas Smad4 was lost in 45.7% cases. The median survival rate with negative and positive PPM1A was 10.9 and 16.8 months, respectively. Loss of PPM1A was significantly associated with larger tumor size and higher stage and was an independent predictor of unfavorable outcomes. Intriguingly, the overall survival of this cohort was divided into 3 groups based on the expression pattern of PPM1A and Smad4, with the Smad4+/PPM1A+ pattern associated with favorable survival, the Smad4+/PPM1A- or Smad4-/PPM1A- pattern associated with unfavorable, and the PPM1A+/Smad4- pattern fell between these 2 groups. In 82 cases with negative Smad4, PPM1A or P-Smad2/3 expression was retained. Using a SMAD4-deficient human PDAC cell line, BxPC3, we further demonstrated that TGF-β1 treatment induced PPM1A and P-Smad2/3 expression in this cell line. PPM1A and Smad4 immunohistochemistry in surgical specimens may provide more accurate prognostic stratification for patients with PDAC.
authors.affiliation: Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Pathology, University of Vermont Medical Center, Burlington, VT 05401.
authors.forename: Michelle X
authors.initials: MX
authors.lastname: Yang
authors.affiliation: Department of Pathology, Huadong Hospital; Fudan University, Shanghai 200040, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ouyang
authors.affiliation: Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Deliang
authors.initials: D
authors.lastname: Fu
authors.affiliation: Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Zude
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Department of Urology, Shanghai 10th People's Hospital, Tongji University, Shanghai 200072, China. Electronic address: gengjiangsn@sina.com.
authors.forename: Jiang
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: tangfeng1996@sina.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Tang
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D002460:Cell Line; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000071636:Protein Phosphatase 2C / Q000378:metabolism*; D034622:RNA Interference; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; C000607456:PPM1A protein, human; D000071636:Protein Phosphatase 2C
keywords: Immunohistochemistry; PPM1A; Pancreatic ductal adenocarcinoma; Phosphatase; Prognosis, marker; Smad4; TGF-β