title: Expression of Wnt and TGF-β pathway components and key adrenal transcription factors in adrenocortical tumors: association to carcinoma aggressiveness.
abstract: Factors controlling benign and malignant adrenocortical tumorigenesis are largely unknown, but several mouse models suggest an important role for inhibin-alpha (INHA). To show that findings in the mouse are relevant to human tumors and clinical outcome, we investigated the expression of signaling proteins and transcription factors involved in the regulation of INHA in human tumor samples⋅ Thirty-one adrenocortical tumor samples, including 13 adrenocortical carcinomas (ACCs), were categorized according to Weiss score, hormonal profile, and patient survival data and analyzed using immunohistochemistry and RT-PCR. Expression of the TGF-β signaling mediator SMAD3 varied inversely with Weiss score, so that SMAD3 expression was lowest in the most malignant tumors. By contrast, SMAD2 expression was upregulated in most malignant tumors. Wnt pathway co-receptors LRP5 and LRP6 were predominantly expressed in benign adrenocortical tumors. In ACCs, expression of transcription factors GATA-6 and SF-1 correlated with that of their target gene INHA. Moreover, the diminished expression of GATA-6 and SF-1 in ACCs correlated with poor outcome. We conclude that the factors driving INHA expression are reduced in ACCs with poor outcome, implicating a role for INHA as a tumor suppressor in humans.
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Finland.
authors.forename: Helka
authors.initials: H
authors.lastname: Parviainen
authors.forename: Anja
authors.initials: A
authors.lastname: Schrade
authors.forename: Sanne
authors.initials: S
authors.lastname: Kiiveri
authors.forename: Renata
authors.initials: R
authors.lastname: Prunskaite-Hyyryläinen
authors.forename: Caj
authors.initials: C
authors.lastname: Haglund
authors.forename: Seppo
authors.initials: S
authors.lastname: Vainio
authors.forename: David B
authors.initials: DB
authors.lastname: Wilson
authors.forename: Johanna
authors.initials: J
authors.lastname: Arola
authors.forename: Markku
authors.initials: M
authors.lastname: Heikinheimo
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002648:Child; D005260:Female; D050993:GATA6 Transcription Factor / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007265:Inhibins / Q000032:analysis; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000032:analysis; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D012042:Registries; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000032:analysis; D051900:Smad3 Protein / Q000032:analysis; D054339:Steroidogenic Factor 1 / Q000032:analysis; D016019:Survival Analysis; D014157:Transcription Factors / Q000032:analysis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000032:analysis*; D051153:Wnt Proteins / Q000032:analysis* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D055815:Young Adult; D051176:beta Catenin / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin; C094377:inhibin-alpha subunit; D007265:Inhibins
keywords: Adenoma; Carcinoma; Inhibin; Signaling pathway; Transcription factor