title: Role of tumor-associated macrophages in the Hexim1 and TGFβ/SMAD pathway, and their influence on progression of prostatic adenocarcinoma.
abstract: BACKGROUND
  Hexamethylene bisacetamide-inducible protein 1 (Hexim1) regulates transforming growth factor-β (TGFβ) activity and turnover of SMAD proteins in a cyclin-dependent kinase 9-dependent way. It does so specifically through inhibiting function of this enzyme and by inhibiting the transcriptional activity of positive transcription elongation factor b (P-TEFb). Tumor-associated macrophages (TAMs) play a role in the progression of prostate adenocarcinomas. We investigated the clinicopathological significance of Hexim1, TGFβ, SMAD2, and SMAD7 expression in prostate adenocarcinoma cells, and assessed associations between TAMs density and these proteins.
  
  
  METHODS
  The cases of 100 patients diagnosed with prostate acinar adenocarcinoma who had undergone radical prostatectomy were retrospectively examined. Each was reviewed for Gleason score, cancer stage, and specific histopathological features. Original slides were re-examined, and new slides were prepared and immunostained with Hexim1, TGFβ, SMAD2, SMAD7 and CD68.
  
  
  RESULTS
  Hexim1 expression was positively correlated with Gleason score, cancer stage, lymphovascular invasion, perineural invasion, extracapsular extension, and positive surgical margin. TAMs density was positively correlated with Gleason score, cancer stage, perineural invasion, extracapsular extension, and positive surgical margin. TAMs density was positively correlated with Hexim1 expression and TGFβ expression. More advanced cancer stage, lymphovascular invasion, perineural invasion, and extracapsular extension were correlated with strong Hexim1 expression, strong SMAD2 expression, and mild SMAD7 expression, respectively. Strong Hexim1 expression, strong TGFβ expression, and mild SMAD7 expression were associated with higher Gleason score. Strong Hexim1 expression was correlated with strong TGFβ expression and mild SMAD7 expression. Strong Hexim1 expression, strong SMAD2 expression, and mild expression of SMAD7 were associated with disease progression. Strong SMAD2 expression was associated with shorter disease-free survival.
  
  
  CONCLUSIONS
  The results suggest that greater TAMs density, strong Hexim1 expression, strong SMAD2 expression, and mild SMAD7 expression play important roles in the progression of prostate adenocarcinoma. Further investigation of these proteins will help facilitate the definitive prognosis of prostate adenocarcinomas. Ultimately, these proteins may be therapeutic targets for patients with prostate cancer.
authors.affiliation: Baskent University Faculty of Medicine, Department of Pathology, 79.sok. No: 7/4 Bahçelievler, 06490 Ankara, Turkey. Electronic address: potkala@hotmail.com.
authors.forename: Alev
authors.initials: A
authors.lastname: Ok Atılgan
authors.affiliation: Baskent University Faculty of Medicine, Department of Pathology, 79.sok. No: 7/4 Bahçelievler, 06490 Ankara, Turkey. Electronic address: handan27@hotmail.com.
authors.forename: B Handan
authors.initials: BH
authors.lastname: Özdemir
authors.affiliation: Baskent University Faculty of Medicine, Department of Pathology, 79.sok. No: 7/4 Bahçelievler, 06490 Ankara, Turkey. Electronic address: edaakcay@gmail.com.
authors.forename: Eda Yılmaz
authors.initials: EY
authors.lastname: Akçay
authors.affiliation: Baskent University Faculty of Medicine, Department of Pathology, 79.sok. No: 7/4 Bahçelievler, 06490 Ankara, Turkey. Electronic address: ozlem-ataol@hotmail.com.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Ataol Demirkan
authors.affiliation: Baskent University Faculty of Medicine, Department of Biostatistics, Bağlıca Kampüsü Eskişehir Yolu 20.km Bağlıca, 06810 Ankara, Turkey. Electronic address: matekindal@gmail.com.
authors.forename: M Agah
authors.initials: MA
authors.lastname: Tekindal
authors.affiliation: Baskent University Faculty of Medicine, Department of Urology, 79.sok. No: 7/4 Bahçelievler, 06490 Ankara, Turkey. Electronic address: ozkardes@baskent.edu.tr.
authors.forename: Hakan
authors.initials: H
authors.lastname: Özkardeş
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000737:chemistry* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D018365:Neoplasm, Residual; D016016:Proportional Hazards Models; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D016601:RNA-Binding Proteins / Q000032:analysis*; D012189:Retrospective Studies; D012307:Risk Factors; D015398:Signal Transduction; D051899:Smad2 Protein / Q000032:analysis*; D051906:Smad7 Protein / Q000032:analysis*; D013997:Time Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000032:analysis*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C476123:HEXIM1 protein, human; D016601:RNA-Binding Proteins; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta
keywords: Hexim1; SMAD2; SMAD7; TGFβ/SMAD pathway; Tumor-associated macrophages (TAMs)