Effects of Polymeric Mucin Expression on Lung Carcinogenesis

聚合粘蛋白表达对肺癌发生的影响

• 批准号: 10369926
• 负责人: Christopher M Evans
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369926
• 关键词: 3-Dimensional; Address; Adenocarcinoma Cell; Affect; Age; Amino Acids; Anabolism; Animals; Apoptosis; Apoptotic; Binding; Biological Assay; Biology; Cancer Biology; Cancer Etiology; Carcinoma; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Cellular biology; Chemoresistance; Chronic Disease; Data; Development; Dimerization; Disease; Distal; Endoplasmic Reticulum; Enzymes; Epithelial; Epithelial Cells; Family; Functional disorder; Gene Expression; Gene Proteins; Genes; Goals; Goblet Cells; Growth; Health; Host Defense; Human; Imaging Techniques; In Vitro; Individual; Inositol; Intervention; KRAS2 gene; KRASG12D; Knockout Mice; Link; Lung; Lung Adenocarcinoma; MUC5AC gene; MUC5B gene; Malignant Neoplasms; Malignant neoplasm of lung; Mammals; Measures; Mediating; Metabolism; Molecular; Mucinous; Mucins; Mucous Membrane; Mucous body substance; Mus; Mutation; Oncogenic; Pathogenesis; Patients; Pharmacology; Polymers; Populations at Risk; Positioning Attribute; Protein Isoforms; Recurrence; Research; Sampling; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Survival Rate; System; Testing; Tissue imaging; Tobacco smoke; Transgenic Mice; Transgenic Model; Translations; Tumor Burden; Tumor Promotion; Urethane; Vascularization; Veterans; Xenograft procedure; animal imaging; cancer cell; cell growth; coping; demographics; disulfide bond; effective therapy; endoplasmic reticulum stress; experience; glycosylation; human tissue; improved; in vivo; inhibitor; innovation; lung carcinogenesis; molecular imaging; mortality; mortality risk; mouse model; neoplastic cell; novel; overexpression; proteostasis; sensor; service member; sugar; tool; treatment strategy; tumor; tumorigenesis

Lung cancer is the leading cause of cancer-related deaths, and risks are disproportionately high in veterans. Lung adenocarcinoma (LUAD) accounts for half of all lung cancer cases, but effective treatments are lacking in part due to an incomplete understanding of LUAD biology. LUAD tumors originate from airway secretory epithelia, and mucin expression is prevalent and associated with LUAD aggressiveness. However, mechanisms by which mucins affect LUAD pathogenesis are poorly understood. The overarching concept of this proposal is that aberrant epithelial growth in LUAD is potentiated by two polymeric mucins--MUC5AC and MUC5B. Though required for airway defense in health, MUC5AC and MUC5B misexpression in LUAD correlates with invasiveness, recurrence, and mortality, especially in patients with activating mutations in KRAS--the most common oncogenic driver of LUAD. We validated MUC5AC causatively in urethane and activated-Kras expression mouse models of LUAD. In animals lacking Muc5ac (‘MUC in humans, ‘Muc’ in mice), tumor number and size decreased by ~50%. The relative tumor-promoting effects of Muc5b on its own or with Muc5ac are not yet known. We seek to close this significance gap here. We also seek to determine molecular mechanisms for polymeric mucin-mediated tumor promotion. Studies by us and by others have identified numerous signals that stimulate LUAD, including mucinous LUAD subtypes. Upstream signaling pathways converge on mucins and their biosynthetic machinery. Individual MUC5AC and MUC5B molecules are extraordinarily large. They multimerize, and they become even more massive through addition of sugars to their central glycosylation domains. Accordingly, protein homeostasis (proteostasis) is tightly regulated during polymeric mucin biosynthesis. Mucin translation, folding, and dimerization occur in the endoplasmic reticulum (ER) and involve formation of hundreds of disulfide bonds. To handle these demands, mammals express a mucous cell specific isoform of the ER stress sensor inositol-requiring enzyme-1 (IRE-1, also called ER-to- nucleus signaling protein, or ERN). ERN1 is ubiquitously expressed and is crucial for ER stress-triggered apoptosis, but an isoform called ERN2 is restricted to mucous cells where it is required for sustaining mucin synthesis despite high levels of ER stress. This adaptation is accomplished by direct binding of ERN2 to ERN1 and subsequent suppression of ERN1-mediated pro-apoptotic signaling. While beneficial for host defense in health, apoptosis suppression could be detrimental in LUAD. We hypothesize that MUC5AC and MUC5B promote epithelial cell growth in LUAD via ERN2-dependent suppression of ER stress-induced apoptosis. The following three Specific Aims are proposed: 1) Test the hypothesis that MUC5AC/Muc5ac and MUC5B/Muc5b promote LUAD and mucinous LUAD; 2) Test the hypothesis that polymeric mucin expression in tumor cells promotes LUAD via ERN2/Ern2 dependent proteostasis dysfunction; 3) Test the hypothesis that polymeric mucin expression promotes ERN2/Ern2-dependent epithelial growth. Studies will utilize novel mouse models, cell lines, and patient samples to focus on significant causative links between mucins, ER stress, and LUAD. Innovative gene-editing tools will be used along with pharmacologic agents as interventions, and state of the art animal, tissue, and molecular imaging techniques will be applied. Completion of these aims has the potential to significantly impact the lives of veterans and their families. Our team comprises experts in mucin and cancer cell biology who are uniquely positioned to address questions that will improve our understanding of KRAS-induced LUAD. Findings could identify MUC5AC, MUC5B, and ERN2 as targets to directly limit LUAD growth and to improve strategies for this common but poorly treatable form of lung cancer.

肺癌是与癌症相关死亡的主要原因，而退伍军人的风险则不成比例。 肺腺癌（LUAD）占所有肺癌病例的一半，但缺乏有效的治疗方法 部分是由于对LUAD生物学的不完全理解。 luad肿瘤起源于气道分泌 上皮和粘蛋白表达很普遍，并且与luad侵略性有关。然而， 粘蛋白影响LUAD发病机理的机制知之甚少。总体的概念 该建议是，LUAD中异常上皮生长是由两种聚合物粘蛋白-MUC5AC和 MUC5B。虽然是健康中防御措施，但在luad中的MUC5AC和MUC5B Missxpression需要 与侵入性，复发和死亡率相关，尤其是在激活突变的患者中 克拉斯 - 卢阿德最常见的致癌驱动力。我们在氨基甲酸酯和 LUAD的活化kras表达小鼠模型。在缺乏MUC5AC的动物中（人类中的“ MUC” 小鼠），肿瘤数量和大小减少了约50％。 MUC5B本身的相对肿瘤促进作用 或与MUC5AC一起尚不清楚。我们试图在这里缩小这一意义差距。我们也试图确定 聚合物粘蛋白介导的肿瘤促进的分子机制。我们和其他人的研究 确定了许多刺激LUAD的信号，包括粘液LUAD亚型。上游信号传导 途径融合了粘蛋白及其生物合成机械。单个MUC5AC和MUC5B分子 非常大。它们多样化，通过将糖添加到 它们的中央糖基化结构域。根据每种 聚合物粘蛋白生物合成。粘蛋白翻译，折叠和二聚化发生在内质网中 （ER）并涉及形成数百种二硫键。为了满足这些要求，哺乳动物表达 ER应力传感器肌醇的胶质溶酶体1（IRE-1，也称为er-to-to-to-to- 核信号蛋白或ERN）。 ERN1无处不在表达，对于ER应力触发至关重要 凋亡，但称为ERN2的同工型仅限于粘液粘蛋白需要的粘液细胞 合成渴望高水平的ER应力。这种适应是通过直接结合ERN2与 ERN1和随后抑制ERN1介导的促凋亡信号传导。虽然对主机有益 在健康方面，抑制细胞凋亡在LUAD中可能有害。我们假设Muc5ac和 MUC5B通过ERN2依赖性抑制ER应激诱导的luAD促进上皮细胞的生长 凋亡。提出了以下三个特定目的：1）检验MUC5AC/MUC5AC和 MUC5B/MUC5B促进luad和粘液luad; 2）检验聚合物粘蛋白表达的假设 在肿瘤细胞中，通过ERN2/ERN2依赖性蛋白质功能障碍促进LUAD； 3）检验以下假设 聚合粘蛋白表达促进ERN2/ERN2依赖性上皮生长。研究将利用新颖 小鼠模型，细胞系和患者样品，专注于粘蛋白之间的显着灾难性联系 压力和luad。创新的基因编辑工具将与制药剂一起使用 将采用干预措施以及艺术动物，组织和分子成像技术的状态。 这些目标的完成有可能显着影响退伍军人及其家人的生活。我们的 团队建立粘蛋白和癌细胞生物学专家 这将提高我们对KRAS引起的LUAD的理解。发现可以识别MUC5AC，MUC5B和 ERN2是直接限制LUAD增长并改善这种常见但无法治疗的策略的目标 肺癌的形式。