title: Reduced insulin-like growth factor I receptor and altered insulin receptor isoform mRNAs in normal mucosa predict colorectal adenoma risk.
abstract: BACKGROUND
  Hyperinsulinemia resulting from obesity and insulin resistance is associated with increased risk of many cancers, but the biology underlying this risk is unclear. We hypothesized that increased mRNA levels of the insulin-like growth factor I receptor (IGFIR) versus the insulin receptor (IR) or elevated ratio of IR-A:IR-B isoforms in normal rectal mucosa would predict adenoma risk, particularly in individuals with high body mass index (BMI) or plasma insulin.
  
  
  METHODS
  Biopsies from normal rectal mucosa were obtained from consenting patients undergoing routine colonoscopy at University of North Carolina Hospitals (Chapel Hill, NC). Subjects with colorectal adenomas were classified as cases (n = 100) and were matched to adenoma-free controls (n = 98) based on age, sex, and BMI. IGFIR and IR mRNA levels were assessed by qRT-PCR, and IR-A:IR-B mRNA ratios by standard PCR. Plasma insulin and crypt apoptosis were measured by ELISA and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), respectively. Logistic regression models examined relationships between receptor mRNAs, BMI, plasma insulin, and adenoma risk.
  
  
  RESULTS
  Unexpectedly, cases were significantly more likely to have lower IGFIR mRNA levels than controls. No overall differences in total IR mRNA or IR-A:IR-B ratios were observed between cases and controls. Interestingly, in patients with high plasma insulin, increased IR-A:IR-B ratio was associated with increased likelihood of having adenomas.
  
  
  CONCLUSIONS
  Our work shows novel findings that reduced IGFIR mRNA and, during high plasma insulin, increased IR-A:IR-B ratios in normal rectal mucosa are associated with colorectal adenoma risk.
  
  
  CONCLUSIONS
  Our work provides evidence supporting a link between IGFIR and IR isoform expression levels and colorectal adenoma risk.
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: M Agostina
authors.initials: MA
authors.lastname: Santoro
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Andres
authors.affiliation: Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Galanko
authors.affiliation: Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sandler
authors.affiliation: Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Temitope O
authors.initials: TO
authors.lastname: Keku
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. empk@med.unc.edu.
authors.forename: P Kay
authors.initials: PK
authors.lastname: Lund
mesh_terms: D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D011972:Receptor, Insulin / Q000096:biosynthesis*
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin