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Cancer-cell-secreted miR-204-5p induces leptin signalling pathway in white adipose tissue to promote cancer-associated cachexia.

ABSTRACT: Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.

SUBMITTER: Hu Y

PROVIDER: S-EPMC10449837 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Cancer-cell-secreted miR-204-5p induces leptin signalling pathway in white adipose tissue to promote cancer-associated cachexia.

Hu Yong Y Liu Liu L Chen Yong Y Zhang Xiaohui X Zhou Haifeng H Hu Sheng S Li Xu X Li Meixin M Li Juanjuan J Cheng Siyuan S Liu Yong Y Xu Yancheng Y Yan Wei W

Nature communications 20230824 1

Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor ...[more]

PMID: 37620316

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Project description:BackgroundCachexia is a wasting syndrome associated with imbalanced energy metabolism and loss of adipose and muscle tissues and contributes to morbidity and mortality in ageing as well as in patients with severe chronic diseases, including cancer. At present, there are no treatments addressing cachexia that have reached validation to be used in the clinic. In this study, we investigate the protective role of SIRT6, an important regulator of energy homeostasis and health preservation, against Lewis lung carcinoma (LLC)-induced cachexia.MethodsSIRT6 levels of serum from gastric cancer patients (n = 22, 65.27 ± 12.50 years old, 40.9% females) and healthy controls (n = 22, 63.50 ± 10.77 years old, 45.4% females) were measured to evaluate the correlation between circulating SIRT6 levels and cancer cachexia development. Ten-week-old SIRT6 transgenic (TG) and wild type (WT) male mice injected with LLC cells (1.5 × 106 per mouse) were used to investigate the protective effects of SIRT6 on cachexia-associated adipose browning and lipolysis and the underlying mechanisms. We explored the effect of SIRT6 on LLC-conditioned medium induced lipolysis in mature adipocytes, differentiated from primary mouse embryonic fibroblasts (MEFs). We evaluated the in vitro effect of a SIRT6 activator by treatment of MDL800.ResultsSIRT6 concentrations were significantly higher in non-cachectic cancer patients (3.41 ± 0.30 ng/mL) compared to cachectic cancer patients (3.20 ± 0.23 ng/mL, p < 0.01), suggesting the negative correlation between SIRT6 level and cachexia in patients with cancer. SIRT6 overexpression significantly ameliorated tumour-induced wasting and energy expenditure in white adipose tissues (eWAT mass loss: 66% in WT vs. 32% in TG; iWAT mass loss: 69% in WT vs. 40% in TG) through suppression of browning and lipolysis. In LLC-induced cachexia, tumour necrosis factor-α receptor 2 (TNFR2) mediated the inhibition of SIRT6 on lipolytic signalling, because the difference in lipolysis between the WT and SIRT6 knockout group was almost eliminated by TNFR2 neutralizing antibody. Increased serum TNFR2 concentration was found in cachectic cancer patients (690.41 pg/mL in non-cachectic vs. 1166.98 pg/mL in cachectic patients, p < 0.05). A selective SIRT6 pharmaceutical activator, MDL800, could completely reverse LLC-induced lipolysis in adipocytes.ConclusionWe found an unexpected beneficial function of SIRT6 in cancer cachexia, demonstrating that increased SIRT6 expression or activity is capable of protecting the host against cachexia-associated tissue wasting, providing a concept of future therapies for cachexia.

Dataset Information

Cancer-cell-secreted miR-204-5p induces leptin signalling pathway in white adipose tissue to promote cancer-associated cachexia.

Publications

Cancer-cell-secreted miR-204-5p induces leptin signalling pathway in white adipose tissue to promote cancer-associated cachexia.

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