Hedgehog-signaling is upregulated in non-producing human adrenal adenomas and antagonism of hedgehog-signaling inhibits proliferation of NCI-H295R cells and an immortalized primary human adrenal cell line.
Hedgehog (Hh)-signaling pathway is important in embryonic development. Activation of Hh-signaling is associated with tumorigenesis. Recent studies demonstrate that Hh-signaling is involved in the development of the adrenal gland in mice and is important in regulating adrenal proliferation. We studied the expression of Sonic hedgehog (SHH), Smoothened (SMO), Patched1 (PTCH1) and GLI family zinc finger 1 (GLI1) in human adrenal and in adrenocortical tumors using immunohistochemistry and semi-quantitative reverse transcriptase-polymerase chain reaction. Modulation of GLI1 and SMO messenger ribonucleic acid (mRNA) expression was investigated with forskolin. The role of Hh-signaling was studied in NCI-H295R cells and in an immortalized primary cell line using the Hh-agonist smoothened agonist (SAG) and the Hh-antagonist cyclopamine. The Hh-pathway components SHH, GLI1, PTCH1 and SMO were detectable in all adrenal glands. While in cortisol-producing adenomas (CPA), Hh-signaling expression levels were comparable to that in normal adrenal cortex, a much higher mRNA expression of GLI1, SMO and SHH was observed in non-producing adenomas (NPA). Interestingly, stimulation of cultured adrenal cells with forskolin led to a decrease in expression of GLI1 and SMO mRNAs. Antagonism of Hh-signaling resulted in a lower proliferation rate of adrenocortical cells, while Hh-agonism had no significant effect on adrenal cell proliferation. Our data show Hh-signaling activity in adult adrenal glands. Activation of the PKA pathway results in lower expression of Hh-signaling proteins. This might explain the lower expression of the Hh components GLI1 and SMO in CPA in comparison to the higher expression in NPA. Hh-signaling might be involved in the tumorigenesis of NPA.
Department of Endocrinology and Diabetology, Medical Faculty, University of Dusseldorf, D-40225 Duesseldorf, Germany; Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Medical Faculty, University of Dusseldorf, D-40225 Duesseldorf, Germany.
Pascal
P
Werminghaus
Matthias
M
Haase
Peter J
PJ
Hornsby
Sven
S
Schinner
Matthias
M
Schott
Ludwik K
LK
Malendowicz
Bernhard J
BJ
Lammers
Peter E
PE
Goretzki
Volker
V
Müller-Mattheis
Markus Giessing
Holger S
HS
Willenberg
D000236:Adenoma / Q000378:metabolism*; D000302:Adrenal Cortex / Q000378:metabolism / Q000473:pathology; D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D061251:Primary Cell Culture; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1
Adrenal; GLI1; Hedgehog; SHH; Tumor