Elucidating the Role of the Desmosome Protein p53 Apoptosis Effector Related to PMP-22 in Growth Hormone Tumors.
Densely granulated and sparsely granulated (SG) growth hormone (GH) pituitary adenomas differ in biological behavior, which may be correlated with their known differences in cytoplasmic keratin distribution and E-cadherin expression. We wanted to explore candidate genes that might further explain this behavior. Exon expression microarray was performed on 21 GH tumors (10 SG and 11 densely granulated) and 20 normal control pituitaries from autopsy. Bioinformatic analyses confirmed a differential molecular signature between normal pituitary and GH tumors as well as between the GH tumor subtypes. There was a consistent downregulation of transcripts involved in the structure and function of the desmosome, including desmoplakin (eightfold), desmoglein 2 (sixfold), plakophilin 2 (sevenfold), and p53 apoptosis effector related to PMP-22 (PERP; sixfold) in SG tumors compared with normal pituitary. PERP is lost in more aggressive SG human GH pituitary tumors. PERP re-expression in GH3 rat GH tumor cells resulted in decreased colony formation compared with vector transfectants, confirming the role of PERP as a tumor suppressor with no effects on proliferation. Increased PERP expression was associated with loss of a survival advantage in a hypoxic environment, as assessed by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (P < 0.05) and cleaved caspase-3 (P < 0.05). Downregulation of desmosomal formation transcripts including PERP may contribute to the aggressive phenotype seen in SG GH pituitary tumors and their behavior in response to surgery and medical therapy.
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, Aurora, Colorado 80045.|Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220.
Katja
K
Kiseljak-Vassiliades
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, Aurora, Colorado 80045.
Taylor S
TS
Mills
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, Aurora, Colorado 80045.
Yu
Y
Zhang
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, Aurora, Colorado 80045.
Mei
M
Xu
Department of Neurosurgery, University of Colorado, Aurora, Colorado 80045.
Kevin O
KO
Lillehei
Department of Neurosurgery, University of Colorado, Aurora, Colorado 80045.|Department of Pathology, University of Colorado, Aurora, Colorado 80045.
B K
BK
Kleinschmidt-DeMasters
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, Aurora, Colorado 80045.|Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220.
Margaret E
ME
Wierman
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics; D003896:Desmosomes / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D046228:Microarray Analysis; D010902:Pituitary Gland / Q000378:metabolism*; D059467:Transcriptome; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C416404:PERP protein, human