miR-379-3p counteracts cancer cachexia through regulation of pyrimidinergic receptor, mitochondrial stress and interferon response.

Borja-Gonzalez, M.; Gonzalez-Ojeda, R.; Sannicandro, A. J.; Su, C.; McCarthy, E. C.; Sanz-Nogues, C.; Dwyer, R. M.; McDonagh, B.; Goljanek-Whysall, K.

doi:10.1101/2025.01.11.632559

bioRxiv · 10.1101/2025.01.11.632559

miR-379-3p counteracts cancer cachexia through regulation of pyrimidinergic receptor, mitochondrial stress and interferon response.

Borja-Gonzalez, M.·Gonzalez-Ojeda, R.·Sannicandro, A. J.·Su, C.·McCarthy, E. C.·Sanz-Nogues, C.·Dwyer, R. M.·McDonagh, B.·Goljanek-Whysall, K.

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Abstract

Cancer cachexia is a highly prevalent wasting syndrome in cancer patients. Inflammation is hallmarks of symptomatic cachexia, however early stages of cachexia are not well understood, including differences between biological sexes. In a mouse model of early cachexia, muscle from males showed strong mitochondrial defects, whereas females were characterized by inflammatory and stress response. We demonstrate a novel link between the increase in purinergic receptor P26Y, and dysregulated Ca2+ homeostasis, mitochondrial dysfunction and damage, and inflammation during early stages of cancer cachexia. Low levels of miR-379-3p were associated with poor survival of patients with lung cancer. Restoring miR-379-3p levels in mice prevented loss of muscle mass and function. miR-379-3p targeted P2r6y and restored mitochondrial content and function, inhibited type II interferon response, and regulated the expression of Ca2+-related and apoptotic markers. This supports miR-379-3p as a hub regulating multiple processes underlying cachexia and represent a therapeutic target for cancer patients.

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Borja-Gonzalez, M., Gonzalez-Ojeda, R., Sannicandro, A. J., Su, C., McCarthy, E. C., Sanz-Nogues, C., Dwyer, R. M., McDonagh, B., Goljanek-Whysall, K.. 2025-01-14. miR-379-3p counteracts cancer cachexia through regulation of pyrimidinergic receptor, mitochondrial stress and interferon response.. https://doi.org/10.1101/2025.01.11.632559

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