Devine Raymond D, Bicer Sabahattin, Reiser Peter J, Wold Loren E
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio.
Am J Physiol Heart Circ Physiol. 2017 Jun 1;312(6):H1154-H1162. doi: 10.1152/ajpheart.00090.2016. Epub 2017 Mar 24.
Cancer cachexia is a progressive wasting disease resulting in significant effects on the quality of life and high mortality. Most studies on cancer cachexia have focused on skeletal muscle; however, the heart is now recognized as a major site of cachexia-related effects. To elucidate possible mechanisms, a proteomic study was performed on the left ventricles of colon-26 (C26) adenocarcinoma tumor-bearing mice. The results revealed several changes in proteins involved in metabolism. An integrated pathway analysis of the results revealed a common mediator in hypoxia-inducible factor-1α (HIF-1α). Work by other laboratories has shown that extensive metabolic restructuring in the C26 mouse model causes changes in gene expression that may be affected directly by HIF-1α, such as glucose metabolic genes. M-mode echocardiography showed progressive decline in heart function by , exhibited by significantly decreased ejection fraction and fractional shortening, along with posterior wall thickness. Using Western blot analysis, we confirmed that HIF-1α is significantly upregulated in the heart, whereas there were no changes in its regulatory proteins, prolyl hydroxylase domain-containing protein 2 (PHD2) and von Hippel-Lindau protein (VHL). PHD2 requires both oxygen and iron as cofactors for the hydroxylation of HIF-1α, marking it for ubiquination via VHL and subsequent destruction by the proteasome complex. We examined venous blood gas values in the tumor-bearing mice and found significantly lower oxygen concentration compared with control animals in the third week after tumor inoculation. We also examined select skeletal muscles to determine whether they are similarly affected. In the diaphragm, extensor digitorum longus, and soleus, we found significantly increased HIF-1α in tumor-bearing mice, indicating a hypoxic response, not only in the heart, but also in skeletal muscle. These results indicate that HIF-1α may contribute, in part, to the metabolic changes that occur during cancer cachexia. We used proteomics and metadata analysis software to identify contributors to metabolic changes in striated muscle during cancer cachexia. We found increased expression of hypoxia-inducible factor-1α in the heart and skeletal muscle, suggesting a potential target for the therapeutic treatment of cancer cachexia.
癌症恶病质是一种进行性消耗性疾病，对生活质量有重大影响且死亡率高。大多数关于癌症恶病质的研究都集中在骨骼肌上；然而，现在心脏被认为是恶病质相关影响的主要部位。为了阐明可能的机制，对携带结肠-26（C26）腺癌肿瘤的小鼠的左心室进行了蛋白质组学研究。结果揭示了参与代谢的蛋白质的几种变化。对结果的综合通路分析揭示了缺氧诱导因子-1α（HIF-1α）中的一种常见介质。其他实验室的研究表明，C26小鼠模型中的广泛代谢重构会导致基因表达的变化，这些变化可能直接受HIF-1α影响，例如葡萄糖代谢基因。M型超声心动图显示心脏功能逐渐下降，表现为射血分数和缩短分数显著降低，以及后壁厚度减小。使用蛋白质免疫印迹分析，我们证实HIF-1α在心脏中显著上调，而其调节蛋白含脯氨酰羟化酶结构域蛋白2（PHD2）和冯·希佩尔-林道蛋白（VHL）没有变化。PHD2需要氧气和铁作为辅助因子来使HIF-1α羟基化，通过VHL标记其进行泛素化，随后被蛋白酶体复合物破坏。我们检查了荷瘤小鼠的静脉血气值，发现在接种肿瘤后第三周，与对照动物相比，氧浓度显著降低。我们还检查了选定的骨骼肌，以确定它们是否受到类似影响。在膈肌、趾长伸肌和比目鱼肌中，我们发现荷瘤小鼠的HIF-1α显著增加，表明不仅在心脏，而且在骨骼肌中都存在缺氧反应。这些结果表明，HIF-1α可能部分导致癌症恶病质期间发生的代谢变化。我们使用蛋白质组学和元数据分析软件来确定癌症恶病质期间横纹肌代谢变化的促成因素。我们发现心脏和骨骼肌中缺氧诱导因子-1α的表达增加，这表明它是癌症恶病质治疗的一个潜在靶点。
