Manipulation of STAT3 Signaling for Muscle Preservation in Cancer Cachexia

描述(申请人提供)：恶病质，或脂肪和骨骼肌的进行性消瘦，尽管有足够的营养，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，容易生病。恶病质困扰着一半以上的癌症患者，占所有癌症相关死亡人数的25%-30%。目前，还没有被批准的治疗癌症肌肉萎缩的有效方法。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，给予IL-6会导致全身消瘦，抑制IL-6可以缓解癌症恶病质。然而，将IL-6与骨骼肌萎缩联系起来的分子机制尚不清楚。我们的长期目标是建立关键的调控途径，以调节癌症中的肌肉萎缩，以开发治疗方法。这项应用的目的是阐明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信号激活STAT3和STAT3靶基因，共同导致蛋白分解增加和肥大减少。最终的结果是肌纤维的浪费。我们基于相当多的初步数据提出了这一假设。在5种恶病质小鼠模型的骨骼肌中，我们观察到了STAT3的磷酸化和已知的STAT3靶基因的表达，包括急性期蛋白。胰腺癌恶病质患者骨骼肌中的IL-6/STAT3转录组也被激活。我们证明，结构性激活的STAT3足以导致肌纤维和正常小鼠骨骼肌的萎缩。此外，STAT3抑制剂的过度表达，消除了IL-6诱导的肌管萎缩。综上所述，这些结果强烈暗示STAT3是癌症恶病质中肌肉萎缩的一个原因。本文提出的研究将确定IL-6/gp130/STAT3信号通路在成熟肌纤维的肌肉生长调节中的作用，无论是在正常生理学中还是在癌症恶病质中。当这些研究完成后，我们将确定癌症恶病质肌肉保存的潜在靶点，以及骨骼肌生长的新调节因素。本研究的具体目的如下：1)确定IL-6/STAT3途径和靶基因在体外肌管肥大和消瘦中的作用；2)确定STAT3和靶基因在正常小鼠和癌症恶病质模型中调节成熟肌纤维生长的功能；3)利用骨骼肌特异性STAT3缺失小鼠和我们的MLC-SOCS3转基因小组，确定骨骼肌STAT3在IL-6诱导的消瘦和癌症恶病质中的作用。 公共卫生相关性：癌症中的肌肉萎缩与高水平的白介素6有关，白介素6是一种血液传播的蛋白质，参与炎症和宿主防御。利用细胞培养和小鼠模型，这项研究将确定白介素6如何激活癌症中的肌肉萎缩，以确定未来的治疗目标。

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.