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Immunohistochemical Analysis of the Metabolic Phenotype of Adrenal Cortical Carcinoma

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Abstract

Metabolic reprogramming is a cellular process contributing to carcinogenesis. However, it remains poorly understood in adrenal cortical carcinoma (ACC), an aggressive malignancy with overall poor prognosis and limited therapeutic options. We characterized the metabolic phenotype of ACC, by examining the immunoprofile of key proteins involved in glucose metabolism, hexokinase (HK1), pyruvate kinase (PKM1, PKM2), succinate dehydrogenase (SDHB), and phospho-S6 ribosomal protein (pS6), in a tissue microarray of 137 adrenal cortical tissue samples. Protein expression was compared between ACC (n = 42), adrenal cortical adenoma (ACA; n = 50), and normal adrenal cortical tissue samples (n = 45). Cytoplasmic expression of HK1 and PKM2 was significantly higher in ACC than in ACA (p < 0.001 and p = 0.014, respectively) or normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). Expression of HK1 and PKM2 was also higher in ACA than in normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). PKM1 expression was overall low in ACC, ACA, and normal samples, although expression of PKM1 was higher in ACC than in ACA (p = 0.027). There was no loss of cytoplasmic granular SDHB expression in our cohort of adrenal cortical tumors, and cytoplasmic expression of pS6 was lower in ACC than in ACA (p = 0.003) or normal adrenal cortical tissue samples (p = 0.008). Significantly, HK1 expression correlated with pyruvate kinase isoform (PKM2 and PKM1) expression (p < 0.001 and p = 0.007, respectively). Although functional validation was not performed, this study provides further evidence that metabolic reprogramming and altered glucose metabolism may occur in a subset of ACC through overexpression of intracellular glycolytic enzymes, notably HK1 and PKM2. The possibility of utilizing the reprogrammed glucose metabolism in ACC for novel therapeutic strategies should be explored in future studies.

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Acknowledgements

The authors would like to thank both Drs. Thomas Giordano and Antonio Marcondes Lerario (University of Michigan Hospital, Michigan Medicine), for assisting the authors to obtain the expression status of HK1, PKM and RPS6 from the TCGA database.

Funding

This work was funded in part by a Canadian Institutes of Health Research (CIHR) New Investigator Foundation Grant FDN-148385 (D.A.W.). D.A.W. holds an Ontario Ministry of Innovation Early Researcher Award.

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Authors and Affiliations

  1. Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G 2C4, Canada

    Kai Duan, Sylvia L. Asa, Daniel A. Winer & Ozgur Mete

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Kai Duan, Daniel A. Winer & Ozgur Mete

  3. Department of Pathology, Recep Tayyip Erdogan University, Rize, Turkey

    Hasan Gucer

  4. Department of Pathology, Ondokuz Mayis University, Samsun, Turkey

    Mehmet Kefeli

  5. Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA

    Sylvia L. Asa

  6. Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, Canada

    Daniel A. Winer

  7. Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, USA

    Daniel A. Winer

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  1. Kai Duan
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  2. Hasan Gucer
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  6. Ozgur Mete
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Correspondence to Ozgur Mete.

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Duan, K., Gucer, H., Kefeli, M. et al. Immunohistochemical Analysis of the Metabolic Phenotype of Adrenal Cortical Carcinoma. Endocr Pathol 31, 231–238 (2020). https://doi.org/10.1007/s12022-020-09624-3

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  • DOI: https://doi.org/10.1007/s12022-020-09624-3

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