Low SGK1 expression in human adrenocortical tumors is associated with ACTH-independent glucocorticoid secretion and poor prognosis.
BACKGROUND
Using single-nucleotide polymorphism analysis, we observed allelic loss of the gene for serum glucocorticoid (GC) kinase 1 (SGK1), a GC-responsive kinase involved in multiple cellular functions, in a subset of cortisol-secreting adenomas.


OBJECTIVE
Our objective was to analyze SGK1 expression in adrenocortical tumors and to further characterize its role in ACTH-independent cortisol secretion, tumor progression, and prognosis.


METHODS
Gene expression levels of SGK1, SGK3, and CTNNB1 (coding for β-catenin) and protein expression levels of SGK1, nuclear β-catenin, and phosphorylated AKT were determined in adrenocortical tumors and normal adrenal glands.


METHODS
A total of 227 adrenocortical tumors (40 adenomas and 187 carcinomas) and 25 normal adrenal tissues were included. Among them, 62 frozen tumor samples were used for mRNA analysis and 203 tumors were investigated on tissue microarrays or full standard slides by immunohistochemistry.


METHODS
We evaluated the relationship between SGK1 mRNA and/or protein levels and clinical parameters.


RESULTS
SGK1 mRNA levels were lower in cortisol-secreting than in nonsecreting tumors (P < 0.005). Nonsecreting neoplasias showed a significant correlation between SGK1 and CTNNB1 mRNA levels (P < 0.001; r = 0.57). Low SGK1 protein levels, but not nuclear β-catenin and phosphorylated AKT, were associated with poor overall survival in patients with adrenocortical carcinoma (P < 0.005; hazard ratio = 2.0; 95% confidence interval = 1.24-3.24), independent of tumor stage and GC secretion.


CONCLUSIONS
Low SGK1 expression is related to ACTH-independent cortisol secretion in adrenocortical tumors and is a new prognostic factor in adrenocortical carcinoma.
Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Oberrduerrbacher-Strasse 6, D-97080 Wuerzburg, Germany. cry_ronchi@yahoo.it
Cristina L
CL
Ronchi
Silviu
S
Sbiera
Ellen
E
Leich
Frédérique
F
Tissier
Sonja
S
Steinhauer
Timo
T
Deutschbein
Martin
M
Fassnacht
Bruno
B
Allolio
D000236:Adenoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D000306:Adrenal Cortex Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D000099184:Serum-Glucocorticoid Regulated Kinases
D000324:Adrenocorticotropic Hormone; D014408:Biomarkers, Tumor; D005938:Glucocorticoids; D006854:Hydrocortisone; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases