Hypoxia Induces Growth Differentiation Factor 15 to Promote the Metastasis of Colorectal Cancer via PERK-eIF2α Signaling.
缺氧通过 perk-eif2 α 信号诱导生长分化因子 15 促进结直肠癌的转移。
- 作者列表："Zheng H","Wu Y","Guo T","Liu F","Xu Y","Cai S
:Hypoxia plays an essential role in orchestrating Epithelial-mesenchymal transition and promoting metastasis of colorectal cancer. However, the underlying mechanisms are still not well elucidated. Here, we present that hypoxic exposure causes endoplasmic reticulum stress and activates the unfolded protein response pathways, which drives GDF15 expression in colorectal cancer cells. Mechanistically, upregulated CHOP led by activated PERK-eIF2α signaling promotes GDF15 transcription via directly binding to its promoter. Further study implicates that hypoxia-induced GDF15 is required for the EMT and invasion of colorectal cancer cells; enforced expression of GDF15 promotes the mitochondrial oxidation of fatty acids in colorectal cancer cells. Moreover, the abrogation of GDF15 results in smaller xenograft tumors in size and impaired metastasis. GDF15 is expressed much more in tumor tissues of CRC patients and displays positive correlations with CHOP and HIF1α in mRNA levels. Our study demonstrates a novel molecular mechanism underlying hypoxia-promoted metastasis of CRC and provides PERK signaling-regulated GDF15 as a new and promising therapeutic target for clinical treatment and drug discovery.
: 缺氧在协调上皮间质转化和促进结直肠癌转移中起着至关重要的作用。然而，潜在的机制仍然没有很好地阐明。在此，我们提出缺氧暴露引起内质网应激，激活未折叠蛋白反应通路，从而驱动 GDF15 在结直肠癌细胞中的表达。机制上，通过激活的 perk-eif2 α 信号上调 CHOP，通过直接与其启动子结合促进 GDF15 转录。进一步的研究表明，缺氧诱导的 GDF15 是结直肠癌细胞 EMT 和侵袭所必需的; GDF15 的强制表达促进了结直肠癌细胞脂肪酸的线粒体氧化。此外，GDF15 的废除导致大小较小的异种移植肿瘤和转移受损。GDF15 在 CRC 患者的肿瘤组织中表达较多，在 mRNA 水平上与 CHOP 和 hif1 α 呈正相关。我们的研究证明了缺氧促进 CRC 转移的新分子机制，并提供了 PERK 信号调节的 GDF15 作为临床治疗和药物发现的新的和有前途的治疗靶点。
METHODS:BACKGROUND:Given the importance of habitual dietary protein intake, distribution patterns and dietary sources in the aetiology of age-related declines of muscle mass and function, the present study examined these factors as a function of sex and age in Irish adults aged 18-90 years comprising The National Adult Nutrition Survey (NANS). METHODS:In total, 1051 (males, n = 523; females, n = 528) undertook a 4-day semi-weighed food diary. Total, body mass relative intake and percentage contribution to total energy intake of dietary protein were determined in addition to protein distribution scores (PDS), as well as the contribution of food groups, animal- and plant-based foods to total protein intake. RESULTS:Total and relative protein intake [mean (SD)] were highest in those aged 18-35 years [96 (3) g day , 1.32 (0.40) g kg day ], with lower protein intakes with increasing age (i.e. in adults aged ≥65 years [82 (22) g, 1.15 (0.34) g kg day , P < 0.001 for both]. Differences in protein intake between age groups were more pronounced in males compared to females. Protein distribution followed a skewed pattern for all age groups [breakfast, 15 (10) g; lunch, 30 (15) g; dinner, 44 (17) g]. Animal-based foods were the dominant protein source within the diet [63% (11%) versus 37% (11%) plant protein, P < 0.001]. CONCLUSIONS:Protein intake and the number of meals reaching the purported threshold for maximising post-prandial anabolism were highest in young adults, and lower with increasing age. For main meals, breakfast provided the lowest quantity of protein across all age categories and may represent an opportunity for improving protein distribution, whereas, in older adults, increasing the number of meals reaching the anabolic threshold regardless of distribution pattern may be more appropriate.
METHODS:BACKGROUND:Low cardiorespiratory fitness (CRF) increases risk of all-cause mortality and cardiovascular events. Periodic CRF assessment can have an important preventive function. OBJECTIVE:To develop a protocol-free method to estimate CRF in daily life based on heart rate (HR) and body acceleration measurements. METHODS:Acceleration and HR data were collected from 37 subjects (M=49%) while performing a standardized laboratory activity protocol (sitting, walking, running, cycling) and during a 5-days free-living monitoring period. CRF was determined by oxygen uptake (VO2max) during maximal exercise testing. A doubly-labeled water validated equation was used to predict total energy expenditure (TEE) from acceleration data. A fitness index was defined as the ratio between TEE and HR (TEE-pulse). Activity recognition techniques were used to process acceleration features and classify sedentary, ambulatory and other activity types. Regression equations based on TEE-pulse data from each activity type were developed to predict VO2max. RESULTS:TEE-pulse measured within each activity type of the laboratory protocol was highly correlated to VO2max (r from 0.74 to 0.91). Averaging the outcome of each activity-type specific equation based on TEE-pulse from the laboratory data led to accurate estimates of VO2max (RMSE: 300.0 mlO2/min or 10%). The difference between laboratory and free-living determined TEE-pulse was 3.7 ± 11% (r =0.85). The prediction method preserved the prediction accuracy when applied to free-living data (RMSE: 367 mlO2/min or 12%). CONCLUSIONS:Measurements of body acceleration and HR can be used to predict VO2max in daily life. Activity-specific prediction equations are needed to achieve highly accurate estimates of CRF.
METHODS:OBJECTIVE:Postprandial dyslipidemia is a common feature of insulin resistant states and contributes to increased cardiovascular disease risk. Recently, bile acids have been recognized beyond their emulsification properties as important signaling molecules that promote energy expenditure, improve insulin sensitivity, and lower fasting lipemia. While bile acid receptors have become novel pharmaceutical targets, their effects on postprandial lipid metabolism remain unclear. Here we investigated the potential role of bile acids in regulation of postprandial chylomicron production and triglyceride excursion. Approach and Results: Healthy C57BL/6 mice were given an intraduodenal infusion of taurocholic acid (TA) under fat-loaded conditions and circulating lipids were measured. Targeting of bile acid receptors was achieved with GW4064, a synthetic agonist to the farnesoid X receptor (FXR), and with deoxycholic acid (DCA), an activator of the Takeda G-protein-coupled receptor 5. TA, GW4064, and DCA treatments all lowered postprandial lipemia. FXR agonism also reduced intestinal triglyceride content and activity of microsomal triglyceride transfer protein, involved in chylomicron assembly. Importantly, TA effects (but not DCA) were largely lost in FXR knockout mice. These bile acid effects are reminiscent of the anti-diabetic hormone glucagon-like peptide-1 (GLP-1). While the GLP-1 receptor agonist exendin-4 retained its ability to acutely lower postprandial lipemia during bile acid sequestration and FXR deficiency, it did raise hepatic expression of the rate limiting enzyme for bile acid synthesis. CONCLUSIONS:Bile acid signaling may be an important mechanism of controlling dietary lipid absorption and bile acid receptors may constitute novel targets for the treatment of postprandial dyslipidemia.