DeJong Cornelis H C, Busquets Sylvia, Moses Alastair G W, Schrauwen Patrick, Ross Jim A, Argiles Josep M, Fearon Kenneth C H
Department of Surgery, University Hospital Maastricht, PO Box 5800, Maastricht NL-6202 AZ, The Netherlands.
Oncol Rep. 2005 Jul;14(1):257-63.
Muscle wasting in experimental cancer cachexia has been associated with increased ubiquitin proteasome proteolytic system activity and increased uncoupling protein (UCP) expression. Increased ubiquitin proteasome pathway activity has also been found in gastric, but not lung, cancer patients. It therefore remains unclear in which patients modulation of this proteolytic system could be a therapeutic target. We investigated markers of systemic inflammation, hypermetabolism and expression of ubiquitin and uncoupling proteins 2 and 3 in muscle of pancreatic cancer patients. Rectus abdominis muscle was sampled from 15 weight-losing pancreatic cancer patients and 11 controls. UCP2 and 3, and ubiquitin mRNA expression were measured by Northern blots and UCP3 protein by Western blotting. Resting energy expenditure and plasma IL-6, sTNF-R and C-reactive protein (CRP) were also measured. Cancer patients had lost 18% of pre-illness stable weight, but were not significantly hypermetabolic compared with controls. IL-6, sTNF-R and CRP levels and ubiquitin 2.4 kb, but not 1.2 kb, mRNA expression were increased in cancer patients. UCP-2 and 3 mRNA and UCP-3 protein were similar in both groups. Weight loss correlated with systemic inflammation and ubiquitin 1.2 and 2.4 kb mRNA expression. Weight loss in pancreatic cancer is associated with systemic inflammation and increased mRNA expression for ubiquitin but not uncoupling proteins in skeletal muscle. The pro-inflammatory network and ubiquitin proteasome pathway may be targets for intervention in pancreatic cancer cachexia.
实验性癌症恶病质中的肌肉消耗与泛素蛋白酶体蛋白水解系统活性增加和解偶联蛋白（UCP）表达增加有关。在胃癌患者中也发现了泛素蛋白酶体途径活性增加，但肺癌患者未发现。因此，尚不清楚在哪些患者中调节这种蛋白水解系统可能成为治疗靶点。我们研究了胰腺癌患者全身炎症、高代谢的标志物以及肌肉中泛素和解偶联蛋白2和3的表达。从15名体重减轻的胰腺癌患者和11名对照者中采集腹直肌样本。通过Northern印迹法测量UCP2和3以及泛素mRNA表达，通过Western印迹法测量UCP3蛋白。还测量了静息能量消耗以及血浆IL-6、可溶性肿瘤坏死因子受体（sTNF-R）和C反应蛋白（CRP）。癌症患者已丧失病前稳定体重的18%，但与对照组相比，其代谢亢进并不显著。癌症患者的IL-6、sTNF-R和CRP水平以及泛素2.4 kb而非1.2 kb的mRNA表达增加。两组中UCP-2和3 mRNA以及UCP-3蛋白相似。体重减轻与全身炎症以及泛素1.2和2.4 kb mRNA表达相关。胰腺癌患者的体重减轻与全身炎症以及骨骼肌中泛素而非解偶联蛋白的mRNA表达增加有关。促炎网络和泛素蛋白酶体途径可能是干预胰腺癌恶病质的靶点。
