OCT4 and NANOG are involved in adrenocortical tumorigenesis

To investigate the involvement of regulators of pluripotency and self-renewal of embryonic stem cells in adrenocortical tumors (ACT).

Clinicopathological data and tissues from 114 ACT patients (96 pediatric-pACT; 18 adults) were analyzed. Normal fetal (n = 33) and postnatal adrenals (n = 26) were used as controls. STAT3, NANOG, SOX2, and OCT4 expression was evaluated by qPCR and IHC. We evaluated intracellular NANOG localization by immunofluorescence and its interaction with beta-catenin after inhibiting the Wnt pathway in a beta-catenin-mutated ACT cell line (NCI-H295).

IHC showed NANOG, OCT4, SOX2, and STAT3 expression in fetal adrenals until mid-pregnancy, disappearing thereafter. Positive OCT4 nuclear staining was found in 32% of pACT samples and was associated with metastasis (OR = 2.28; 95% CI:1.13-4.59; P < 0.05). ACTs presented lower SOX2 mRNA expression (P < 0.01). STAT3 mRNA levels were higher in cortisol-secreting ACT (P = 0.01) and in adult adenomas (P < 0.01). NANOG mRNA was higher in p.S45P CTNNB1 mutated ACT (P < 0.01). NCI-H295 cells exhibit nuclear NANOG expression, which was decreased by inhibiting the Wnt/beta-catenin pathway (P < 0.01).

Markers of pluripotency and self-renewal of embryonic stem cells are expressed until mid-pregnancy, contributing to the adult adrenal stem cell niche. They are absent postnatally but are expressed in a subset of ACT. Specifically, pS45P beta-catenin-mutated ACTs express more NANOG. Increased OCT4 expression in pACT is associated with worse prognosis, and inhibiting the Wnt/beta-catenin pathway in these cells impairs NANOG expression.