Manipulation of STAT3 Signaling for Muscle Preservation in Cancer Cachexia

描述（由申请人提供）：恶病质，或尽管营养充足但脂肪和骨骼肌仍进行性消耗，是癌症的毁灭性并发症。恶病质导致虚弱、生活质量下降、对治疗反应差和对疾病的易感性。恶病质折磨着超过一半的癌症患者，并导致25-30%的癌症相关死亡。目前，还没有批准的有效治疗癌症肌肉萎缩的方法。在癌症患者中，恶病质和死亡率与血清IL-6水平升高密切相关。在小鼠中，IL-6给药引起全身性消耗，IL-6抑制改善癌症恶病质。然而，IL-6和骨骼肌萎缩的分子机制尚不清楚。我们的长期目标是建立介导癌症肌肉萎缩的关键调控途径，以开发治疗方法。本申请的目的是阐明IL-6导致癌症中骨骼肌萎缩的机制。我们的假设是成熟肌纤维中的IL-6信号传导激活了STAT 3和STAT 3靶基因，它们共同导致蛋白水解增加和肥大减少。最终的结果是肌纤维消耗。我们把这个假设建立在相当多的初步数据的基础上。在5种恶病质小鼠模型的骨骼肌中，我们观察到磷酸化的STAT 3和已知STAT 3靶基因的表达，包括急性期蛋白。IL-6/STAT 3转录组在胰腺癌恶病质患者的骨骼肌中也被激活。我们发现，组成性激活的STAT 3足以导致肌纤维和正常小鼠骨骼肌的消耗。此外，STAT 3抑制剂的过表达消除了IL-6诱导的肌管消耗。总之，这些结果强烈暗示STAT 3是癌症恶病质中肌肉萎缩的致病因素。本文提出的研究将明确确定IL-6/gp 130/STAT 3信号通路在正常生理和癌症恶病质中成熟肌纤维肌肉生长调节中的作用。当这些研究完成时，我们将确定癌症恶病质中肌肉保护的潜在目标，以及骨骼肌生长的新调节剂。这项研究的具体目标如下：1）确定IL-6/STAT 3途径和靶基因在体外肌管肥大和消耗中的作用，2）确定STAT 3和靶基因在正常小鼠和癌症恶病质小鼠模型中调节成熟肌纤维生长的功能，和3）使用骨骼肌特异性STAT 3缺失小鼠和我们的MLC-SOCS 3转基因组确定骨骼肌STAT 3对IL-6诱导的消耗和癌症恶病质的贡献。 公共卫生相关性：癌症中的肌肉萎缩与高水平的白细胞介素-6有关，白细胞介素-6是一种参与炎症和宿主防御的血液传播蛋白。使用细胞培养和小鼠模型，这项研究将确定白细胞介素-6如何激活癌症中的肌肉萎缩，以确定未来的治疗靶点。

DESCRIPTION (provided by applicant): Cachexia, or progressive wasting of fat and skeletal muscle despite adequate nutrition, is a devastating complication of cancer. Cachexia results in weakness, diminished quality of life, poor response to therapy, and susceptibility to illness. Cachexia afflicts more than half of all cancer patients and is responsible for 25-30% of all cancer-related deaths. Currently, there are no approved effective treatments for muscle wasting in cancer. In cancer patients, cachexia and mortality correlate closely with elevated serum IL-6 levels. In mice, IL-6 administration causes systemic wasting and IL-6 inhibition ameliorates cancer cachexia. However, the molecular mechanisms linking IL-6 and skeletal muscle wasting are unknown. Our long term goal is to establish the key regulatory pathways that mediate muscle wasting in cancer for the purpose of developing therapeutics. The objective of this application is to elucidate the mechanisms by which IL-6 results in skeletal muscle wasting in cancer. Our hypothesis is that IL-6 signaling in mature myofibers activates STAT3 and STAT3 target genes that together result in increased proteolysis and reduced hypertrophy. The net result is myofiber wasting. We base this hypothesis on considerable preliminary data. In skeletal muscle of 5 mouse models of cachexia, we have observed phosphorylated STAT3 and expression of known STAT3 target genes, including acute phase proteins. The IL-6/STAT3 transcriptome is also activated in skeletal muscle from patients with pancreatic cancer cachexia. We show that constitutively activated STAT3 is sufficient to cause wasting in myofibers and normal mouse skeletal muscle. Furthermore, over-expression of STAT3 inhibitors, abrogated IL-6-induced wasting of myotubes. Taken together, these results strongly implicate STAT3 as a causative factor in muscle wasting in cancer cachexia. The studies proposed here will determine definitively the role of the IL-6/gp130/STAT3 signaling pathway in muscle growth regulation in mature myofibers, both in normal physiology and in cancer cachexia. When these studies are complete, we will have identified potential targets for muscle preservation in cancer cachexia, as well as new regulators of skeletal muscle growth. The specific aims of this study are as follows: 1) Determine the role of the IL-6/STAT3 pathway and target genes in myotube hypertrophy and wasting in vitro, 2) Determine STAT3 and target gene functions in regulating mature myofiber growth in normal mice and in mouse models of cancer cachexia, and 3) Determine the contribution of skeletal muscle STAT3 to IL-6 induced wasting and cancer cachexia using skeletal muscle specific STAT3 null mice and our panel of MLC-SOCS3 transgenics. PUBLIC HEALTH RELEVANCE: Muscle wasting in cancer is associated with high levels of Interleukin-6, a blood-borne protein involved in inflammation and host defense. Using cell culture and mouse models, this study will determine how Interleukin- 6 activates muscle wasting in cancer in order to identify future therapeutic targets.