The anti-tumorigenic activity of A2M-A lesson from the naked mole-rat.
Susanne KurzRené ThiemeRonny AmbergMarco GrothHeinz-Georg JahnkePhilipp PierohLars-Christian HornMarlen KolbKlaus HuseMatthias PlatzerDaniela VolkeFaramarz DehghaniAnton BuzdinKathrin EngelAndrea RobitzkiRalf HoffmannInes GockelGerd BirkenmeierPublished in: PloS one (2017)
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.
Keyphrases
- cell adhesion
- pi k akt
- cell proliferation
- cell cycle arrest
- signaling pathway
- poor prognosis
- papillary thyroid
- epithelial mesenchymal transition
- oxidative stress
- induced apoptosis
- gene expression
- squamous cell
- squamous cell carcinoma
- risk assessment
- binding protein
- climate change
- dna methylation
- type diabetes
- genome wide
- rna seq
- human health
- newly diagnosed
- high fat diet induced