Sonic hedgehog signaling is active in human adrenal cortex development and deregulated in adrenocortical tumors.
BACKGROUND
The sonic hedgehog (SHH) pathway plays a key role in rodent adrenal cortex development and is involved in tumorigenesis in several human tissues, but data in human adrenal glands are limited.


OBJECTIVE
The objectives of the study were to analyze the involvement of the SHH pathway in human adrenal development and tumorigenesis and the effects of SHH inhibition on an adrenocortical tumor (ACT) cell line.


METHODS
Expression of SHH pathway components was evaluated by immunohistochemistry in 51 normal adrenals (33 fetal) and 34 ACTs (23 pediatric) and by quantitative PCR in 81 ACTs (61 pediatric) and 19 controls (10 pediatric). The effects of SHH pathway inhibition on gene expression and cell viability in the NCI-H295A adrenocortical tumor cell line after cyclopamine treatment were analyzed.


RESULTS
SHH pathway proteins were present in fetal and postnatal normal adrenals and showed distinct patterns of spatiotemporal expression throughout development. Adult adrenocortical carcinomas presented with higher expression of PTCH1, SMO, GLI3, and SUFU compared with normal adult adrenal cortices. Conversely, pediatric ACTs showed lower mRNA expression of SHH, PTCH1, SMO, GLI1, and GLI3 compared with normal pediatric adrenal cortices. In vitro treatment with cyclopamine resulted in decreased GLI3, SFRP1, and CTNNB1 mRNA expression and β-catenin staining as well as decreased cell viability.


CONCLUSIONS
The SHH pathway is active in human fetal and postnatal adrenals, up-regulated in adult adrenocortical carcinomas, and down-regulated in pediatric ACTs. SHH pathway antagonism impaired cell viability. The SHH pathway is deregulated in ACTs and might provide a new target therapy to be explored.
School of Medicine (D.C.G., L.F.L., L.M.M., C.A.S., C.E.M., L.G.T., S.T., F.R., A.C.M., L.N.R., M.C., S.R.R.A.), Ribeirao Preto Medical School-University of Sao Paulo, 14090-900 Ribeirao Preto, Brazil; School of Medicine (M.C.B.V.F., A.C.L.), University of Sao Paulo, 01246-903 Sao Paulo, Brazil; and Boldrini Children's Center (J.A.Y., S.R.B., I.A.C., M.J.M.), 13083-210 Campinas, Brazil.
Débora C
DC
Gomes
Letícia F
LF
Leal
Livia M
LM
Mermejo
Carlos A
CA
Scrideli
Carlos E
CE
Martinelli
Maria C B V
MC
Fragoso
Ana C
AC
Latronico
Luis G
LG
Tone
Silvio
S
Tucci
Jose A
JA
Yunes
Izilda A
IA
Cardinalli
Maria J
MJ
Mastellaro
Silvia R
SR
Brandalise
Fernando
F
Ramalho
Ayrton C
AC
Moreira
Leandra N
LN
Ramalho
Margaret
M
de Castro
Sonir R R
SR
Antonini
D000302:Adrenal Cortex / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics
D053823:Hedgehog Proteins