Whole genome expression profiling of glucose-dependent insulinotropic peptide (GIP)- and adrenocorticotropin-dependent adrenal hyperplasias reveals novel targets for the study of GIP-dependent Cushing's syndrome.
BACKGROUND
The mechanisms responsible for the ectopic adrenal expression of glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) in GIP-dependent Cushing's syndrome (CS) are unknown. Chronic adrenal stimulation by ACTH in Cushing's disease or GIP in GIP-dependent ACTH-independent macronodular adrenal hyperplasia both lead to the induction of genes implicated in adrenal proliferation and steroidogenesis.


OBJECTIVE
The objective of the study was to identify genes differentially expressed specifically in GIP-dependent CS that could be implicated in the ectopic expression of GIPR.


METHODS
We used the Affymetrix U133 plus 2.0 microarray oligochips to compare the whole genome expression profile of adrenal tissues from five cases of GIP-dependent bilateral ACTH-independent macronodular adrenal hyperplasia with CS, one case of GIP-dependent unilateral adenoma with CS, five cases of ACTH-dependent hyperplasias, and a pool of adrenals from 62 normal individuals.


RESULTS
After data normalization and statistical filtering, 723 genes with differential expression were identified, including 461 genes or sequences with a known functional implication, classified in eight dominant functional classes. Specific findings include repression of perilipin, the overexpression of 13 G protein-coupled receptors, and the potential involvement of Rho-GTPases. We also isolated 94 probe sets potentially linked to the formation of GIP-dependent nodules adjacent to the diffuse hyperplasia. These included probe sets related to the linker histone H1 and repression of RXRa and CCND2. The expression profiles for eight genes were confirmed by real-time RT-PCR.


CONCLUSIONS
This study identified an extensive series of potentially novel target candidate genes that could be implicated in the molecular mechanisms of ectopic expression of the GIPR as well as in the multistep progression of GIP-dependent CS.
Lampron
Antoine
A
Department of Medicine, Hôtel-Dieu du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
Bourdeau
Isabelle
I
Hamet
Pavel
P
Tremblay
Johanne
J
Lacroix
André
A
D000293:Adolescent; D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D003480:Cushing Syndrome / Q000235:genetics* / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D006965:Hyperplasia; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011964:Receptors, Gastrointestinal Hormone / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; D012313:RNA; C041086:gastric inhibitory polypeptide receptor