Prognostic Biomarkers for ZIP4-mediated Cachexia in Pancreatic Cancer

 描述(由申请人提供)：本提案的总体目标是描述ZIP4介导的致命胰腺癌恶病质的预后标志物。了解这些标记物对于治疗患有肌肉萎缩的PC患者至关重要。恶病质肌肉萎缩常与PC有关。目前针对癌细胞的治疗在减少恶病质和改善患者生存方面收效甚微，强调了寻找新的预测肌肉萎缩的生物标志物和开发针对PC肌肉分解代谢的新疗法的重要性。这项提案的新概念是，ZIP4是PC中高表达的锌转运蛋白，是PC生长、肌肉损耗和生存的关键调节因子。多年来，我们一直致力于ZIP4在PC中的作用。我们的团队是第一个证明ZIP4在大多数PC患者(80%)中过度表达并参与PC发病的小组。沉默ZIP4可增强PC细胞对化疗和缺锌诱导的细胞凋亡的敏感性，延长生存期，提示ZIP4是PC的预后标志物和治疗靶点。我们最近的研究表明，ZIP4参与了PC的肌肉萎缩。然而，ZIP4如何促进肌肉萎缩尚不清楚。在这项研究中，基于我们最近的发现，我们的目标是确定ZIP4的预后价值，识别ZIP4激活的分解代谢介质，并阐明ZIP4介导PC肌肉萎缩的机制(S)。在我们新开发的外科异种移植小鼠模型中，我们观察到，手术切除肿瘤与降低PC细胞中ZIP4水平相结合，显著提高了存活率，减少了体重减轻和肌肉损耗。我们还证明，PC细胞中ZIP4水平的降低可以改善由于p38MAPK活性减弱和随后的Avergin1/MAFbx上调而导致的肌肉萎缩，这在以前被证明是介导其他类型肿瘤细胞诱导的肌肉分解代谢的。这项研究的中心假设是，ZIP4通过明显增强p38MAPK介导的分解代谢途径的激活，通过增加特定的热休克蛋白的表达和释放来介导PC诱导的肌肉萎缩，这种ZIP4增强的恶病质途径可以作为这种阴郁疾病的预后标志。我们提出了三个具体目标：通过检测切除肿瘤中ZIP4与血清Hsp70/90水平、肌肉中p38MAPK激活的分解代谢途径和PC患者临床预后(生存)的相关性，来评估ZIP4及其相关分解代谢途径在PC中的预后价值。我们将通过ZIP4依赖的Hsp70和Hsp90的表达/释放来确定PC是否在两个独立的PC恶病质小鼠模型中诱导肌肉萎缩。我们将通过激活p38MAPK介导的肌肉分解代谢的Hsp70/90来阐明PC导致肌肉萎缩的机制。ZIP4诱导的恶病质是影响PC生长和存活的一个新的信号通路。所提出的研究将有助于明确该致癌轴的调节机制，并评估ZIP4恶病质轴在PC中的预后价值。这项研究将对PC患者产生立竿见影的影响。

 DESCRIPTION (provided by applicant): The overall objective of this proposal is to delineate prognostic markers for ZIP4-mediated cachexia in lethal pancreatic cancer (PC). Understanding these markers is critical to therapeutic interventions for PC patients suffering from muscle wasting. Cachectic muscle wasting is frequently associated with PC. Current therapies aimed at the cancer cells provide little benefit in reducing cachexia and improving patient survival, highlighting the importance of finding new prognostic biomarkers for muscle wasting and developing new therapy targeting muscle catabolism in PC. The new concept in this proposal is that ZIP4, a zinc transporter highly expressed in PC, is a key regulator of PC growth, muscle wasting and survival. We have been working on the role of ZIP4 in PC for many years. Our group is the first one to show that ZIP4 is overexpressed in a majority of PC patients (>80%) and contributes to PC pathogenesis. Silencing ZIP4 sensitizes PC cells to chemotherapy and zinc deficiency-induced apoptosis, and prolongs survival, which suggests that ZIP4 is a prognostic marker and therapeutic target for PC. Our recent studies suggest that ZIP4 mediates muscle wasting in PC. However, how ZIP4 promotes muscle wasting is not clear. In this proposal, on the basis of our recent findings we aim to determine the prognostic value of ZIP4, identify ZIP4-activated catabolic mediators, and elucidate the mechanism(s) through which ZIP4 mediates muscle wasting in PC. In our newly developed surgical xenograft mouse model, we observed that surgical removal of tumors combined with lowering ZIP4 levels in PC cells significantly improved survival and reduced body weight loss and muscle wasting. We also demonstrated that reduced ZIP4 levels in PC cells ameliorated muscle wasting due to attenuated p38 MAPK activation and subsequent atrogin1/MAFbx up regulation, which was shown previously to mediate the muscle catabolism induced by other types of tumor cells. The central hypothesis of the proposed study is that ZIP4 mediates PC-induced muscle wasting through a distinctly enhanced activation of the p38 MAPK-mediated catabolic pathway by increasing expression and release of specific heat shock proteins and this ZIP4-enhanced cachexia pathway could serve as a prognostic marker for this dismal disease. Three specific aims are proposed: We will evaluate the prognostic values of ZIP4 and related catabolic pathway in PC by examining the correlation of ZIP4 in resected tumors with serum Hsp70/90 levels, p38 MAPK-activated catabolic pathway in muscles and clinical outcome (survival) of PC patients. We will determine whether PC induces muscle wasting in two independent mouse models of PC cachexia through ZIP4-dependent expression/release of Hsp70 and Hsp90. We will delineate the mechanisms of PC induced muscle wasting through Hsp70/90 activation of p38 MAPK-mediated muscle catabolism. ZIP4-induced cachexia represents a novel signaling pathway impacting PC growth and survival. The proposed studies will help define the mechanism regulating this oncogenic axis and evaluate the prognostic value of the ZIP4-cachexia axis in PC. This study will have an immediate impact for PC patients.