使用基于适配体的发现平台鉴定胰腺癌恶病质的潜在血清蛋白生物标志物和信号通路。

Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform.

作者信息

Narasimhan Ashok, Shahda Safi, Kays Joshua K, Perkins Susan M, Cheng Lijun, Schloss Katheryn N H, Schloss Daniel E I, Koniaris Leonidas G, Zimmers Teresa A

机构信息

Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

出版信息

Cancers (Basel). 2020 Dec 15;12(12):3787. doi: 10.3390/cancers12123787.

Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC ≥ |1.5|, ≤ 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity ( ≥ |0.50|, ≤ 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia.

胰腺导管腺癌（PDAC）患者会遭受使人虚弱且致命的体重减轻，即恶病质。开发相关疗法需要生物标志物来诊断和监测恶病质；然而，目前尚无此类标志物在临床中使用。通过Somascan技术，我们检测了30例PDAC患者和11例对照者的约1300种血浆蛋白。我们发现60种蛋白在局部PDAC中具有特异性，46种在转移性PDAC中具有特异性，67种在癌症体重减轻超过5%时出现（倍数变化≥|1.5|，P≤0.05）。有6种蛋白在癌症分期方面具有共性（升高：生长分化因子15、基质金属蛋白酶组织抑制因子1、白细胞介素1受体样蛋白1；降低：CC趋化因子配体22、淀粉样前体蛋白、C型凝集素结构域家族1成员B）。有4种蛋白在局部病变/恶病质方面具有共性（补体C1r、蛋白激酶Cγ、弹性蛋白酶、骨硬化蛋白：均呈相反调节）以及4种在转移性病变/恶病质方面具有共性（丝氨酸蛋白酶抑制剂A6、血小板衍生生长因子受体α、胰蛋白酶2、胰蛋白酶1：均呈一致变化），这表明分期和恶病质状态在分子层面可能是可分离的。我们发现71种蛋白与恶病质严重程度通过体重减轻分级、体重减轻、骨骼肌指数和骨密度相关（相关性≥|0.50|，P≤0.05），包括一些已知的恶病质介质/标志物（瘦素、肌肉生长抑制素、白蛋白）以及新蛋白（如淋巴管内皮透明质酸受体1、补体C7、凝血因子Ⅱ）。通路、相关性和上游调节因子分析确定了已知机制（如白细胞介素6、蛋白酶体、线粒体功能障碍）和新机制（如Wnt信号通路、自然杀伤细胞）。总体而言，本研究为验证提供了基础，并深入了解了癌症恶病质的潜在机制。