IGF2 role in adrenocortical carcinoma biology
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ORIGINAL ARTICLE
IGF2 role in adrenocortical carcinoma biology Sofia S. Pereira1,2,3 Mariana P. Monteiro3 Madalena M. Costa3 Ângela Moreira3 Marco G. Alves4,5 Pedro F. Oliveira1 Ivana Jarak5 Duarte Pignatelli 1,2,6 ●
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Received: 10 March 2019 / Accepted: 20 July 2019 © The Author(s) 2019
Abstract Purpose Clinical 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. Methods IGF2 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. Results IGF2 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. Conclusions IGF2 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. Keywords Adrenocortical tumors Adrenocortical carcinomas IGF2 Hallmarks of cancer ●
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Supplementary information The online version of this article (https:// doi.org/10.1007/s12020-019-02033-5) contains supplementary material, which is available to authorized users.
majority of ACT are benign, non-functioning and incidentally discovered during imaging studies performed for unrelated clinical reasons [2]. In contrast to adrenocortical adenomas (ACA), adrenocortical carcinomas (ACC) are rare, the majority are diagnosed in an advanced stage and usually have a poor prognosis [1]. Detailed knowledge of molecular alterations that underlie the malignant transformation of benign cells, as well as the identification of the specific cell cycle alterations found in cancer cells that are
* Duarte Pignatelli [email protected]
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Biology and Genetics of Reproduction, Department of Microscopy, Laboratory of Cell Biology, Multidisciplinary Unit for Biomedic
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