title: Attenuated RORC expression in the presence of EMT progression in somatotroph adenomas following treatment with somatostatin analogs is associated with poor clinical recovery.
abstract: Somatostatin analogs (SA) have been established as the first line medical treatment for acromegaly, but following long-term treatment, SA normalizes GH and IGF-I levels in only 40-60% of patients. The epithelial marker E-cadherin plays a crucial role in the epithelial mesenchymal transition (EMT) and is associated with a poor response to SA treatment. We hypothesized that the characterization of transcripts regulated by SA in somatotroph adenomas with high and low E-cadherin expression may identify signaling pathways and mediators that can explain the poor response to SA treatment. We performed a microarray analysis of sixteen adenomas with different levels of E-cadherin and SA treatment to identify regulated transcripts. Candidate transcripts were further explored in vivo in sixty-five adenomas, and interactions between SA treatment and EMT progression on mRNA expression profiles and associations with clinical recovery were assessed. Finally, the effects of SA treatment on adenoma cells in vitro from acromegalic patients were determined. Microarray analysis of selected adenomas with differential E-cadherin expression, as a marker of EMT progression, identified 172 genes that displayed differential expression that was dependent on SA treatment. The validation of selected candidates in the entire cohort identified 9 transcripts that showed an interaction between E-cadherin expression and SA treatment. Further analysis of the impact of these genes suggests that attenuated RORC expression in somatotroph adenomas is associated with increased tumor size and a blunted clinical response. Our study indicates that attenuated RORC may be involved in the poor clinical response to SA treatment in patients with acromegaly.
authors.affiliation: Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway. tove.lekva@medisin.uio.no
authors.forename: Tove
authors.initials: T
authors.lastname: Lekva
authors.forename: Jens Petter
authors.initials: JP
authors.lastname: Berg
authors.forename: Ansgar
authors.initials: A
authors.lastname: Heck
authors.forename: Stine
authors.initials: S
authors.lastname: Lyngvi Fougner
authors.forename: Ole Kristoffer
authors.initials: OK
authors.lastname: Olstad
authors.forename: Geir
authors.initials: G
authors.lastname: Ringstad
authors.forename: Jens
authors.initials: J
authors.lastname: Bollerslev
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics*; D015282:Octreotide / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D017211:Treatment Failure
chemical_list: D015820:Cadherins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; C539900:RORC protein, human; D013004:Somatostatin; D015282:Octreotide