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bioRxiv · 10.1101/2021.03.10.433216

Immunity Depletion, Telomere Imbalance, and Cancer-associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Caloric Restriction

Maestri, E.·Duszka, K.·Kuznetsov, V. A.
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Abstract

Systematic analysis of calorie restriction (CR) mechanisms and pathways in cancer biology has not been carried out, leaving therapeutic benefits unclear. Using a systems biology approach and metadata analysis, we studied gene expression changes in the response of normal mouse duodenum mucosa (DM) to short-term (2-weeks) 25% CR as a biological model. We found a high similarity of gene expression profiles in human and mouse DM tissues. Surprisingly, 26% of the 467 CR responding differential expressed genes (DEGs) in mice consist of cancer-associated genes--most never studied in CR contexts. The DEGs were enriched with over-expressed cell cycle, oncogenes, and metabolic reprogramming pathways (MRP) that determine tissue-specific tumorigenesis, cancer, and stem cell activation; tumor suppressors and apoptosis genes were under-expressed. DEG enrichments suggest a misbalance in telomere maintenance and activation of metabolic pathways playing dual (anti-cancer and pro-oncogenic) roles. Immune system genes (ISGs) consist of 37% of the total DEGs; the majority of ISGs are suppressed, including cell-autonomous immunity and tumor immune evasion controls. Thus, CR induces MRP suppressing multiple immune mechanics and activating oncogenic pathways, potentially driving pre-malignant and cancer states. These findings change the paradigm regarding the anti-cancer role of CR and may initiate specific treatment target development.

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Maestri, E., Duszka, K., Kuznetsov, V. A.. 2021-03-11. Immunity Depletion, Telomere Imbalance, and Cancer-associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Caloric Restriction. https://doi.org/10.1101/2021.03.10.433216

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