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Expression of a mutant prohibitin from the aP2 gene promoter leads to obesity-linked tumor development in insulin resistance-dependent manner

Oncogene volume 35, pages 4459–4470 (2016)Cite this article

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Abstract

A critical unmet need for the study of obesity-linked cancer is the lack of preclinical models that spontaneously develop obesity and cancer sequentially. Prohibitin (PHB) is a pleiotropic protein that has a role in adipose and immune functions. We capitalized on this attribute of PHB to develop a mouse model for obesity-linked tumor. We achieved this by expressing Y114F-PHB (m-PHB) from the aP2 gene promoter for simultaneous manipulation of adipogenic and immune signaling functions. The m-PHB mice develop obesity in a sex-neutral manner, but only male mice develop impaired glucose homeostasis and hyperinsulinemia similar to transgenic mice expressing PHB. Interestingly, only male m-PHB mice develop histiocytosis with lymphadenopathy, suggesting that metabolic dysregulation or m-PHB alone is not sufficient for the tumor development and that both are required for tumorigenesis. Moreover, ovariectomy in female m-PHB mice resulted in impaired glucose homeostasis, hyperinsulinemia and consequently tumor development similar to male m-PHB mice. These changes were not observed in sham-operated control m-Mito-Ob mice, further confirming the role of obesity-related metabolic dysregulation in tumor development in m-PHB mice. Our data provide a proof-of-concept that obesity-associated hyperinsulinemia promotes tumor development by facilitating dormant mutant to manifest and reveals a sex-dimorphic role of PHB in adipose–immune interaction or immunometabolism. Targeting PHB may provide a unique opportunity for the modulation of immunometabolism in obesity, cancer and in immune diseases.

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Acknowledgements

We thank Anamarija Perry, Department of Pathology, University of Manitoba, Canada for help with tumor characterization and Nivida Mishra for proofreading the manuscript. We were supported by the Natural Sciences and Engineering Research Council of Canada, Canadian Breast Cancer Foundation, Manitoba Health Research Council (MHRC) and Canada Foundation for Innovation. GPP-M is a recipient of an MHRC Postdoctoral Fellowship Award.

Author contributions

SRA generated the aP2-PHB construct, performed genotyping, measured hormone and adipokine levels in serum and contributed to all experiments involving animals. KHN performed histological and immunohistochemical analysis, measured hormone levels and contributed to all experiments involving animals. GPP-M analyzed protein samples. BLGN contributed to the data interpretation and writing of the manuscript. SM contributed to the experimental design, data analysis and interpretation and writing of the manuscript.

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Author notes

  1. S R Ande and K H Nguyen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

    S R Ande, K H Nguyen, G P Padilla-Meier, B L G Nyomba & S Mishra

  2. Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada

    S Mishra

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  1. S R Ande
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  3. G P Padilla-Meier
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  4. B L G Nyomba
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Correspondence to S Mishra.

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Ande, S., Nguyen, K., Padilla-Meier, G. et al. Expression of a mutant prohibitin from the aP2 gene promoter leads to obesity-linked tumor development in insulin resistance-dependent manner. Oncogene 35, 4459–4470 (2016). https://doi.org/10.1038/onc.2015.501

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