The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells

Baek, Amy E.; Yu, Yen Rei A.; He, Sisi; Wardell, Suzanne E.; Chang, Ching Yi; Kwon, Sang-Hoon; Pillai, Ruchita V.; McDowell, Hannah B.; Thompson, J. Will; Dubois, Laura G.; Sullivan, Patrick M.; Kemper, Jongsook Kim; Gunn, Michael D.; McDonnell, Donald P.; Nelson, Erik R.

doi:10.1038/s41467-017-00910-z

Cited by 281 publications

(253 citation statements)

References 63 publications

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“…Furthermore, we discovered cholesterol metabolite, 27hydroxycholesterol level change was shocking in HADHA-treated HCC cells. As reported, it could not only regulate the target genes controlling cholesterol, glucose, and fatty acid metabolism of liver but also increase the proliferation of various cancer cell [45,46].…”

Section: Discussionmentioning

confidence: 75%

MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming

et al. 2020

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Background: MicroRNA-612 (miR-612) has been proven to suppress EMT, stemness, and tumor metastasis of hepatocellular carcinoma (HCC) via PI3K/AKT2 and Sp1/Nanog signaling. However, its biological roles on HCC progression are far from elucidated. Methods: We found direct downstream target of miR-612, hadha by RNA immunoprecipitation and sequencing. To explore its biological characteristic, potential molecular mechanism, and clinical relevance in HCC patients, we performed several in-vitro and in-vivo models, as well as human tissue chip.Results: Ectopic expression of miR-612 could partially reverse the level of HADHA, then suppress function of pseudopods, and diminish metastatic and invasive potential of HCC by lipid reprogramming. In detail, miR-612 might reduce invadopodia formation via HADHA-mediated cell membrane cholesterol alteration and accompanied with the inhibition of Wnt/β-catenin regulated EMT occurrence. Our results showed that the maximum oxygen consumption rates (OCR) of HCCLM3 miR-612-OE and HCCLM3 hadha-KD cells were decreased nearly by 40% and 60% of their counterparts (p < 0.05). The levels of acetyl CoA were significantly decreased, about 1/3 (p > 0.05) or 1/2 (p < 0.05) of their controls, in exogenous miR-612 or hadha-shRNA transfected HCCLM3 cell lines. Besides, overexpression of hadha cell lines had a high expression level of total cholesterol, especially 27-hydroxycholesterol (p < 0.005). SREBP2 protein expression level as well as its downstream targets, HMGCS1, HMGCR, MVD, SQLE were all deregulated by HADHA. Meanwhile, the ATP levels were reduced to 1/2 and 1/4 in HCCLM3 miR-612-OE (p < 0.05) and HCCLM3 hadha-KD (p < 0.01) respectively. Moreover, patients with low miR-612 levels and high HADHA levels had a poor prognosis with shorter overall survival.Conclusion: miR-612 can suppress the formation of invadopodia, EMT, and HCC metastasis and by HADHAmediated lipid programming, which may provide a new insight of miR-612 on tumor metastasis and progression.

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Section: Discussionmentioning

confidence: 75%

MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming

et al. 2020

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“…Although the CH25H product 25HC can act as a ligand for activating the nuclear liver X receptor (which can play anti-tumorigenic roles), a number of oxysterol-elicited effects were shown to be independent of the liver X receptor (reviewed in Traversari et al, 2014). Importantly, another ligand of this receptor, 27hydroxycholesterol, was recently shown to promote the metastatic process by acting on immune cells (Baek et al, 2017). Notably, IFN did not induce the expression of CYP27A, which catalyzes production of 27-hydroxycholesterol.…”

Section: Discussionmentioning

confidence: 99%

An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles

et al. 2019

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Graphical AbstractHighlights d Tumor-derived extracellular vesicles (TEV) downregulate IFNAR1 and CH25H d CH25H acts to restrict TEV uptake and limit the education of healthy cells d Downregulation of CH25H in normal cells promotes melanoma metastasis d Disruption of TEV uptake and education by reserpine elicits anti-metastatic effects SUMMARY Tumor-derived extracellular vesicles (TEV) ''educate'' healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake. Low CH25H levels in leukocytes from melanoma patients correlated with poor prognosis. Mice incapable of downregulating the IFN receptor and Ch25h were resistant to TEV uptake, TEV-induced pre-metastatic niche, and melanoma lung metastases; however, ablation of Ch25h reversed these phenotypes. An anti-hypertensive drug, reserpine, suppressed TEV uptake and disrupted TEV-induced formation of the pre-metastatic niche and melanoma lung metastases. These results suggest the importance of CH25H in defense against education of normal cells by TEV and argue for the use of reserpine in adjuvant melanoma therapy.

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“…Possible mechanistic pathways underlying the association between obesity and breast cancer risk and survival involve chronic inflammation, steroid hormones, up-regulation of insulin-like growth factors, hyperinsulinemia or insulin resistance, and altered immune function [14, 31]. Dysregulation of theses pathways may influence cellular processes that promote tumor initiation and progression [32].…”

Section: Obesity and Breast Cancermentioning

confidence: 99%

Obesity, Dietary Factors, Nutrition, and Breast Cancer Risk

Seiler

Chen

Brown

et al. 2018

Curr Breast Cancer Rep

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Purpose of Review To synthesize the critical role of obesity-associated inflammation, dietary factors, and nutrition in determining breast cancer risk. Recent Findings Obesity-associated inflammation is strongly linked to breast cancer risk and progression, largely via two processes: inflammatory pathways and dysregulated metabolism. Cytokine production in excess adipose tissues creates a chronic inflammatory microenvironment, which favors tumor development. Lifestyle factors, including diet, have long been recognized as important determinants of breast cancer risk and mortality. Summary Obesity increases the risk of developing breast cancer in both pre- and postmenopausal women and also negatively affects breast cancer recurrence and survival. Poor dietary habits characterized by the high intake of refined starches, sugar, and both saturated and trans-saturated fats, as well as the low intake of omega-3 fatty acids, natural antioxidants, and fiber, modulate inflammation and, thereby, appear to be linked to increased risk of breast cancer and mortality.

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The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells

Cited by 281 publications

References 63 publications

MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming

MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming

An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles

Obesity, Dietary Factors, Nutrition, and Breast Cancer Risk

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