Lipidomic Profiles of Plasma Exosomes Identify Candidate Biomarkers for Early Detection of Hepatocellular Carcinoma in Patients with Cirrhosis.
Lipidomic Profiles of Plasma Exosomes Identify Candidate Biomarkers for Early Detection of Hepatocellular Carcinoma in Patients with Cirrhosis.
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DOI：
10.1158/1940-6207.capr-20-0612
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
Beretta L
中科院分区：
文献类型：
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作者：
Sanchez JI;Jiao J;Kwan SY;Veillon L;Warmoes MO;Tan L;Odewole M;Rich NE;Wei P;Lorenzi PL;Singal AG;Beretta L
迫切需要新的生物标志物用于HCC患者的监测。外泌体和它们的脂质含量，特别是，代表潜在的有价值的非侵入性诊断生物标志物。我们从72名胰腺炎患者的血浆中分离了外泌体，其中包括31名HCC患者。使用超高分辨率质谱法处理外泌体和未分级血浆用于非靶向脂质组学。共鉴定出2,864种脂质，分属52类。外泌体分离和HCC诊断对脂质谱有显著影响。与非HCC外泌体相比，HCC外泌体中富集了10种脂质类别。在35%的HCC外泌体中检测到二溶血心磷脂，但在非HCC外泌体中没有检测到二溶血心磷脂（p<0.001）。心磷脂和鞘氨醇具有最高的差异效应（倍数变化分别为133.08，q=0.001和38.57，q<0.001）。Logistic回归分析显示，外泌体鞘氨醇、二溶血心磷脂、溶血磷脂酰丝氨酸和（O-酰基）-1-羟基脂肪酸的高丰度与HCC密切相关（OR [95% CI]：271.1 [14.0-5251.9]，p<0.001; 46.5 [2.3-939.9]，p=0.012; 14.9 [4.3-51.2]，p<0.001; 10.3 [3.2-33.1]，p<0.001）。与非HCC外泌体相比，HCC外泌体中耗尽了四种脂质类别。在逻辑回归分析中，硫苷脂和酰基Glc谷甾醇酯检测缺失与HCC密切相关（OR [95% CI]：215.5 [11.5-4035.9]，p<0.001; 26.7 [1.4-528.4]，p=0.031）。这些HCC相关的外泌体脂质组成的变化反映了甘油磷脂代谢、逆行内源性大麻素信号传导和铁凋亡的改变。总之，这项研究确定了早期检测HCC的候选生物标志物以及可能有助于肿瘤发展和进展的外泌体中改变的途径。
Novel biomarkers for HCC surveillance in cirrhotic patients are urgently needed. Exosomes and their lipid content in particular, represent potentially valuable noninvasive diagnostic biomarkers. We isolated exosomes from plasma of 72 cirrhotic patients, including 31 with HCC. Exosomes and unfractionated plasma were processed for untargeted lipidomics using ultra-high-resolution mass spectrometry. A total of 2,864 lipid species, belonging to 52 classes, were identified. Both exosome fractionation and HCC diagnosis had significant impact on the lipid profiles. Ten lipid classes were enriched in HCC exosomes compared to non-HCC exosomes. Dilysocardiolipins were detected in 35% of the HCC exosomes but in none of the non-HCC exosomes (p<0.001). Cardiolipins and sphingosines had the highest differential effects (fold change of 133.08, q=0.001 and 38.57, q<0.001, respectively). In logistic regression analysis, high abundances of exosomal sphingosines, dilysocardiolipins, lysophosphatidylserines and (O-acyl)-1-hydroxy fatty acids were strongly associated with HCC (OR [95% CI]: 271.1 [14.0–5251.9], p<0.001; 46.5 [2.3–939.9], p=0.012; 14.9 [4.3–51.2), p<0.001; 10.3 [3.2–33.1], p<0.001). Four lipid classes were depleted in HCC exosomes compared to non-HCC exosomes. In logistic regression analysis, lack of detection of sulfatides and acylGlcSitosterol esters was strongly associated with HCC (OR [95% CI]: 215.5 [11.5–4035.9], p<0.001; 26.7 [1.4–528.4], p=0.031). These HCC-associated changes in lipid composition of exosomes reflected alterations in glycerophospholipid metabolism, retrograde endocannabinoid signaling and ferroptosis. In conclusion, this study identified candidate biomarkers for early detection of HCC as well as altered pathways in exosomes that may contribute to tumor development and progression.