Prognostic Biomarkers for ZIP4-mediated Cachexia in Pancreatic Cancer

ZIP4 介导的胰腺癌恶病质的预后生物标志物

• 批准号: 9052445
• 负责人: MIN LI
• 金额: $ 10.93万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052445
• 关键词: Apoptosis; Attenuated; Body Weight decreased; Cachexia; Cancer Center; Cancer Patient; Catabolism; Clinical; Conditioned Culture Media; Development; Diagnosis; Disease; Excision; FBXO32 gene; Genetic Engineering; Growth; Heat shock proteins; Human; Knock-out; Lead; MAP Kinase Gene; MAPK14 gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Modeling; Mus; Muscle; Muscle Fibers; Muscular Atrophy; Oncogenic; Operative Surgical Procedures; Outcome; Pancreatectomy; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathway interactions; Patients; Prognostic Marker; Resected; Role; Serum; Signal Pathway; Staging; Testing; Therapeutic Intervention; Tumor Biology; Up-Regulation; Work; Xenograft procedure; Zinc deficiency; base; cancer cachexia; cancer cell; chemotherapy; cohort; effective therapy; improved; inhibitor/antagonist; knock-down; mouse model; neoplastic cell; new therapeutic target; novel; novel diagnostics; novel marker; novel therapeutics; overexpression; pancreatic cancer cells; prognostic value; public health relevance; survival outcome; therapeutic target; tumor; zinc-binding protein

 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.

 描述（由申请人提供）：本提案的总体目标是描述致死性胰腺癌（PC）中ZIP 4介导的恶病质的预后标志物。了解这些标志物对于患有肌肉萎缩的PC患者的治疗干预至关重要。恶病质性肌肉萎缩通常与PC有关。目前针对癌细胞的疗法在减少恶病质和改善患者生存方面几乎没有益处，这突出了寻找肌肉萎缩的新预后生物标志物和开发针对PC中肌肉萎缩的新疗法的重要性。该提案中的新概念是ZIP 4，一种在PC中高度表达的锌转运蛋白，是PC生长，肌肉萎缩和存活的关键调节因子。多年来，我们一直致力于ZIP 4在PC中的作用。我们的研究小组是第一个表明ZIP 4在大多数PC患者（>80%）中过表达并有助于PC发病机制的研究小组。沉默ZIP 4使PC细胞对化疗和缺锌诱导的细胞凋亡和细胞存活敏感，这表明ZIP 4是PC的预后标志物和治疗靶点。我们最近的研究表明，ZIP 4介导PC中的肌肉萎缩。然而，ZIP 4如何促进肌肉萎缩尚不清楚。在这个提议中，基于我们最近的研究结果，我们的目标是确定ZIP 4的预后价值，鉴定ZIP 4激活的分解代谢介质，并阐明ZIP 4介导PC肌肉萎缩的机制。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结合降低PC细胞中的ZIP 4水平显著提高了存活率，并减少了体重减轻和肌肉萎缩。我们还证明，PC细胞中ZIP 4水平的降低改善了肌肉萎缩，这是由于减弱了p38 MAPK激活和随后的atrogin 1/MAFbx上调，这在以前被证明介导由其他类型的肿瘤细胞诱导的肌肉紧张素。提出的研究的中心假设是，ZIP 4介导的PC诱导的肌肉萎缩，通过明显增强激活p38 MAPK介导的分解代谢途径，通过增加表达和释放特定的热休克蛋白，这种ZIP 4增强恶病质途径可以作为这种令人沮丧的疾病的预后标志物。提出了三个具体目标：我们将通过检查切除肿瘤中ZIP 4与血清Hsp 70/90水平、肌肉中p38 MAPK激活的分解代谢途径和PC患者的临床结局（生存期）的相关性，评估ZIP 4和相关分解代谢途径在PC中的预后价值。我们将确定PC是否通过ZIP 4依赖的Hsp 70和Hsp 90的表达/释放在两个独立的PC恶病质小鼠模型中诱导肌肉萎缩。我们将通过Hsp 70/90激活p38 MAPK介导的肌钙蛋白酶来阐明PC诱导的肌肉萎缩的机制。ZIP 4诱导的恶病质代表了影响PC生长和存活的新信号传导途径。这些研究将有助于确定调节这一致癌轴的机制，并评估ZIP 4-恶病质轴在PC中的预后价值。这项研究将对PC患者产生直接影响。