PO.MCB09.06 · 分子与细胞生物学
游离脂肪酸破坏胆固醇稳态通过调控CCL20促进结肠癌
Disruption in cholesterol homeostasis by free fatty acid promote colon cancer by modulating CCL20
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摘要 Abstract
中文摘要
背景：结直肠癌（CRC）表现出代谢灵活但失调的脂质稳态，涉及脂质合成增加、脂肪酸摄取改变、储存增强以及膜和胆固醇池的重塑。这些过程与炎症信号网络相互作用，可能支持癌症进展。CCL20是一种在富含脂质和炎症性CRC微环境中升高的趋化因子，已被认为参与肿瘤进展，但其与脂质代谢调控的关系仍不清楚。本研究考察脂质代谢与CCL20信号之间可能的相互作用，特别是其对CRC模型中脂质累积、膜生物物理特性和胆固醇代谢程序的影响。
方法：将CRC细胞系（Caco2、DLD1、HCT116）暴露于链长（C12、C16）和饱和度（C16:0、C18:1(9)）不同的游离脂肪酸（FFAs）。通过ELISA定量CCL20的产生。使用月桂酸（C12）和棕榈酸（C16）评估FFA摄取。通过归一化至细胞大小的BODIPY平均荧光强度评估脂质累积。使用Laurdan广义偏振（GP）和荧光成像测量膜流动性。测量了总胆固醇、细胞内和分泌的胆固醇，以及酯化与游离胆固醇的比值，同时检测胆固醇相关酶（包括HMGCR、SOAT2和SREBP2）的表达。纳入过表达CCL20的HCT116细胞以验证CCL20的作用。
结果：数据表明不同链长的FFAs可能以不同方式调控CCL20表达。在具有不同CCL20信号的CRC细胞系中观察到FFA内化和累积的独特模式以及膜流动性的变化。发现胆固醇水平和关键代谢酶的表达与CCL20的调控相关。
结论：这些发现确立了CRC细胞中脂质代谢与CCL20表达和功能之间的明确联系。正在进行的研究旨在验证这些观察结果，并建立一个CCL20驱动的结直肠癌代谢调控的统一模型。
查看英文原文 English abstract
Background: Colorectal cancer (CRC) displays metabolically flexible but dysregulated lipid homeostasis, involving increased lipid synthesis, altered fatty acid uptake, enhanced storage, and remodeling of membranes and cholesterol pools. These processes interact with inflammatory signaling networks and may support cancer progression. CCL20, a chemokine elevated in lipid-rich and inflammatory CRC microenvironments, has been implicated in tumor progression, but its relationship with lipid metabolic regulation remains unclear. This study examines possible interactions between lipid metabolism and CCL20 signaling, and specifically its effects on lipid accumulation, membrane biophysics, and cholesterol metabolic programs in CRC models.
Methods: CRC cell lines (Caco2, DLD1, HCT116) were exposed to free fatty acids (FFAs) differing in chain length (C12, C16) and saturation (C16:0, C18:1(9)). CCL20 production was quantified by ELISA. FFA uptake was assessed using Lauric acid (C12) and palmitic acid (C16). Lipid accumulation was assessed by BODIPY mean fluorescence intensity normalized to cell size. Membrane fluidity was measured using Laurdan generalized polarization (GP) and fluorescence imaging. Total, cellular and secreted cholesterol, as well as ratio of esterified and free cholesterol ratios were measured alongside expression of cholesterol-associated enzymes, including HMGCR, SOAT2, and SREBP2. CCL20-overexpressing HCT116 cells were included to validate effects of CCL20.
Results: Data indicate that FFAs of differing lengths may variably modulate CCL20 expression. Distinct patterns of FFA internalization and accumulation, and membrane fluidity shifts were observed in CRC cell line with differential CCL20 signaling. Levels of cholesterol and expression of key metabolic enzymes were found to be associated with CCL20 modulation.
Conclusions: These findings establish a clear link between lipid metabolism and CCL20 expression and function in CRC cells. Ongoing studies aim to validate these observations and develop a unified model of CCL20-driven metabolic regulation in colorectal cancer.
利益披露 Disclosure
J. Muralidharan, None..
A. Bhatt, None..
J. M. Mims, None..
G. Hughes, None..
P. Marcelline, None..
S. Bae, None..
S. Singh, None..
H. Mir, None.