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PLoS One. 2017 Dec 27;12(12):e0189514. doi: 10.1371/journal.pone.0189514. eCollection 2017.

The anti-tumorigenic activity of A2M-A lesson from the naked mole-rat.

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Institute of Biochemistry, University of Leipzig, Medical Faculty, Leipzig, Germany.
Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Medical Faculty, Leipzig, Germany.
Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany.
Centre for Biotechnology and Biomedicine, Molecular Biological-Biochemical Processing Technology, University of Leipzig, Germany.
Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, Halle (Saale), Germany.
Institute of Pathology, Division of Breast, Gynaecological and Perinatal Pathology, University of Leipzig, Leipzig, Germany.
Center for Biotechnology and Biomedicine, University of Leipzig, Leipzig, Germany.
Pharmaceutical Artificial Intelligence Department, Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, Baltimore, Maryland, United States of America.
Department of Pathway Engineering for Cancer Research, OmicsWay Corp., Walnut, CA, United States of America.
National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, 1, Akademika Kurchatova sq., Moscow, Russia.


Cancer resistance is a major cause for longevity of the naked mole-rat. Recent liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M) and cell adhesion molecules, which contribute to the naked mole-rat's cancer resistance. Notably, A2M is known to dramatically decrease with age in humans. We hypothesize that this might facilitate tumour development. Here we found that A2M modulates tumour cell adhesion, migration and growth by inhibition of tumour promoting signalling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR-21, in vitro and in tumour xenografts. A2M increases the expression of CD29 and CD44 but did not evoke EMT. Transcriptome analysis of A2M-treated tumour cells, xenografts and mouse liver demonstrated a multifaceted regulation of tumour promoting signalling pathways indicating a less tumorigenic environment mediated by A2M. By virtue of these multiple actions the naturally occurring A2M has strong potential as a novel therapeutic agent.

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