IGF2 role in adrenocortical carcinoma biology

Abstract

PurposeClinical outcomes of adrenocortical carcinomas (ACC) could be improved by using novel treatment targets based on the recent advances of tumor biology knowledge. Insulin-like growth factor 2 (IGF2) protein expression is usually 8–80 fold higher in ACC when compared to normal adrenal glands (N-AG) or adrenocortical adenomas (ACA), despite the fact that the biological features of high vs. low IGF2 expressing ACC have not yet been well characterized. Our goal was to understand the IGF2 role in ACC biology by focusing in several cancer hallmarks, including cell proliferation, viability, invasion, and metabolism.MethodsIGF2 immunohistochemistry expression was evaluated in ACC (n = 13), non-functioning adrenocortical adenoma (ACAn) (n = 14), and N-AG (n = 9). The effects of IGF2 (50, 100 ng/mL) in cell proliferation, viability, invasion, and metabolism, as well as in MAPK/ERK and mTOR pathways activation and N-cadherin expression, were evaluated in the ACC human cell line H295R.ResultsIGF2 expression was increased in ACC compared to ACAn and N-AG. Exposure to 100 ng/mL of IGF2 increased H295R cell proliferation and viability. mTOR inhibition reverted IGF2 triggered cell proliferation and viability while MEK/MAPK/ERK inhibition only reverted IGF2 effects on cell proliferation. IGF2 at a 50 ng/mL concentration increased the glycolytic flux and decreased glutamine consumption.ConclusionsIGF2 is an excellent marker to differentiate ACC from ACAn. In addition, IGF2 was demonstrated to influence adrenocortical cancer cell proliferation, metabolism, and viability, but not the cell invasion. These data support that different IGF2 concentrations in ACC can be responsible for different biological behaviors of ACC.

Key MicroRNA’s and Their Targetome in Adrenocortical Cancer

“…IGF2 binds to the membrane tyrosine kinase receptor IGF Receptor Type 1 (IGF-1R), leading to receptor autophosphorylation and binding of the insulin receptor substrate 1 (IRS-1). Tyrosine phosphorylation of IRS-1 activates the phosphatidylinositol-3-kinase(PI3K)/serine/threonine protein kinase B (Akt) and mammalian target of rapamycin(mTOR) pathway as well as the Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-related kinase (ERK) pathways, potentiating cellular proliferation and viability in ACC cell models [44].…”

Autophagy suppression of trophoblast cells induces pregnancy loss by activating decidual NK cytotoxicity and inhibiting trophoblast invasion

“…Among the 12 potential genes related to NK function, IGF-2 was the most significantly upregulated one in ATG5-RNAi group (Fig. 4a), which was also reported to be degraded by autophagy [25]. To verify whether autophagy in trophoblasts regulated the phenotype of dNK cells dependent on IGF-2, dNK cells were co-cultured with rapamycin pretreated trophoblasts, adding IGF-2 in the medium or not.…”

Autophagy suppression of trophoblast cells induces pregnancy loss by activating decidual NK cytotoxicity and inhibiting trophoblast invasion

“…Among the 12 potential genes related to NK function, IGF-2 was the most significantly upregulated in ATG5-RNAi group (Fig. 4a), which was also reported to be degraded by autophagy [25]. To verify whether autophagy in trophoblasts regulated the phenotype of dNK cells dependent on IGF-2, dNK cells were co-cultured with rapamycin pretreated trophoblasts, adding IGF-2 in the medium or not.…”