Abstract
AimAdrenocortical carcinoma (ACC) is characterized with excessive hormone production. We therefore investigated expression of hormone-related genes in ACC.ResultsWe queried status of 14 key genes directly involved in adrenal hormone production and found HSD17B4 expression was upregulated in 39% of ACC cases on top of all queried genes. Overexpression of HSD17B4 was significantly associate with a normo-hormonal phenotype. Constitutive HSD17B4 expression was higher in ACC cell line NCI-H295R than in adrenocortical small cell carcinoma cell line SW13. NCI-H295R cells with HSD17B4-knockdown (KD) demonstrated significantly inhibited proliferation, increased apoptosis, and increased cell cycle arrest. Enrichment analysis for mRNA expression in ACC samples with or without HSD17B4 overexpression showed significant change in p53 pathway. Replenish of HSD17B4 in SW13 cells and knockdown of HSD17B4 in H295R cells confirmed alterations in MDM4, ATR, and IE24 with alterations more contrasting in H295R cells. HSD17B4-KD inhibited cell invasion, migration and anchorage independent growth of NCI-H295R cells, but not of SW13 cells.Materials and MethodsClinical and genetic data of ACC samples were reproduced from the ACC dataset of The Cancer Genome Atlas (TCGA) database using cBioPortal. Genes participating in adrenal hormone production were queried. Association between gene status and hormone release were studied and in vitro assays using RNA interference were carried out.ConclusionsOverexpression of HSD17B4 exerted tumor suppressive function in adrenocortical carcinoma and was not related to hormone excess. Crosstalk between HSD17B4 and p53 warrants further investigation.
Highlights
Adrenocortical carcinoma (ACC) is a rare endocrine malignance at a prevalence of approximately 0.7 to 2 per million people [1, 2]
We queried status of 14 key genes directly involved in adrenal hormone production and found HSD17B4 expression was upregulated in 39% of ACC cases on top of all queried genes
Constitutive HSD17B4 expression was higher in ACC cell line NCI-H295R than in adrenocortical small cell carcinoma cell line SW13
Summary
Adrenocortical carcinoma (ACC) is a rare endocrine malignance at a prevalence of approximately 0.7 to 2 per million people [1, 2]. While the disease is surgically resectable at earlier stages, it is substantially aggressive at advanced stages. The cortex of adrenal gland secretes a variety of vital hormones which are produced in excessive amount in ACC and causes severe symptoms. Starting from cholesterol, the adrenal cortex produces cortisol, mineralocortisol, and sex hormones in general under meticulous mediation from the central-peripheral axis via series of enzymes. In the malignant setting, dysregulated hormone excess could lead www.impactjournals.com/oncotarget to disrupted balance in metabolism, electrolyte equilibrium and sexual appearance. The predominant type of hormone dysregulation in ACC, may substantially compromise immune response, allow viral replication, and bring cortisol-related multi-systematic complications, all being severe health problems [6,7,8]. Whether excessive hormone secretion is intrinsically procarcinogenic or stands solely as a byproduct facilitating ACC to a minor extent, remains unclear. The answer lies in part in the contribution of genes encoding those enzymes for hormone production as well as in cases without hormone excess, which occur in approximately 40% of cases [9]
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