Mechanistic difference of NF-kappaB in lung physiology and tumorigenesis

NF-κB在肺生理和肿瘤发生中的机制差异

• 批准号: 10689678
• 负责人: Zhaoxia Qu
• 金额: $ 38.2万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689678
• 关键词: Acetylation; Age Months; Atlases; Automobile Driving; Cancer Etiology; Cancer Patient; Cancer cell line; Cells; Cessation of life; ChIP-seq; Chemoresistance; Clinic; Clinical; Clinical Treatment; Combined Modality Therapy; Data; Databases; Development; Disease; Disease remission; Ectopic Expression; Embryo; Epithelium; Family; Genes; Histologic; Host Defense; Human; Immune; Immune response; Immunity; Immunology procedure; Immunotherapy; In Vitro; Inflammatory; Investigation; Knock-in Mouse; Knock-out; Knockout Mice; LIM Domain; Link; Lung; Lung Neoplasms; Lung infections; Malignant Neoplasms; Malignant neoplasm of lung; Modification; Molecular; Mus; NF-kappa B; Normal Cell; Nuclear; Oncogenic; PD-1 blockade; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pattern; Pharmaceutical Preparations; Physiological; Physiology; Play; Prognosis; Proteins; RELA gene; Regulation; Repression; Resistance; Role; Safety; Signal Induction; Signal Transduction; Specificity; Survival Rate; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tumor Promoters; Tumor Suppressor Proteins; Virus Diseases; Woman; anti-PD-1; cancer therapy; cell growth; chemotherapeutic agent; chemotherapy; conditional knockout; effective therapy; epigenetic drug; fighting; immune checkpoint blockade; improved; improved outcome; in vivo; innovation; lung cancer cell; lung tumorigenesis; member; men; mimetics; mouse model; neoplastic cell; novel; p65; pharmacologic; prevent; programmed cell death protein 1; response; restoration; single-cell RNA sequencing; synergism; therapy resistant; transcription factor; tumor; tumorigenesis; ubiquitin-protein ligase

Abstract The transcription factor NF-κB is critically important for tumorigenesis and therapeutic resistance but we have been unable to successfully target it for clinical treatment due to its equally important roles in physiology and host defense in particular. Teasing apart these functions of NF-κB will overcome this barrier resulting in a powerful means to fight cancer. While the core mechanism driving NF-κB activation has been well defined and is the same under most physiological and oncogenic conditions, the mechanistic difference in physiological vs. oncogenic NF-κB still remains a conundrum. Recently, we have demonstrated, for the first time, that extrinsic/ inflammatory and intrinsic/oncogenic signals induce different activation patterns and different forms of NF-κB in normal lung cells and lung cancer cells. Moreover, we have identified, also for the first time, the PDZ-LIM domain-containing protein PDLIM2 that selectively suppresses the ‘oncogenic’ but not ‘physiologic’ activation of NF-κB and can be targeted as mono- or combination therapy in murine models of lung cancer. Based on these novel discoveries, in this proposal we will determine the molecular mechanisms by which PDLIM2 acts as a determinant of NF-κB function. We will also dissect the roles and molecular mechanisms of this regulation of the ‘oncogenic’ and ‘physiologic’ activation of NF-κB in lung tumorigenesis and physiological host defense against pulmonary infection. These studies are significant, because we know NF-κB is a strong tumor promoter linked to almost all human cancers but cannot currently be targeted in the clinic given its physiological importance. Also, these studies have both conceptual and technical innovations regarding NF-κB and cancer, since they open new avenues to study the differential regulation and action of NF-κB in cancer and physiology, and may lead to new clinically feasible approaches to selectively target pathogenic NF-κB for cancer therapy.

抽象的 转录因子 NF-κB 对于肿瘤发生和治疗耐药至关重要，但我们有 由于其在生理学中同样重要的作用，无法成功地将其用于临床治疗 尤其是主机防守。梳理 NF-κB 的这些功能将克服这一障碍，从而产生 对抗癌症的有力手段。虽然驱动 NF-κB 激活的核心机制已被明确定义并且 在大多数生理和致癌条件下是相同的，生理与致癌条件下的机制差异。 致癌性 NF-κB 仍然是一个难题。最近，我们首次证明了外在/ 炎症和内在/致癌信号在细胞中诱导不同的激活模式和不同形式的 NF-κB 正常肺细胞和肺癌细胞。此外，我们还首次确定了 PDZ-LIM 含有结构域的蛋白质 PDLIM2，选择性抑制“致癌”激活，但不抑制“生理”激活 NF-κB 的作用，可作为肺癌小鼠模型的单一或联合疗法。基于 这些新发现，在本提案中我们将确定 PDLIM2 作用的分子机制 作为 NF-κB 功能的决定因素。我们还将剖析这种调节的作用和分子机制 NF-κB 在肺肿瘤发生和宿主生理防御中的“致癌”和“生理”激活 预防肺部感染。这些研究意义重大，因为我们知道 NF-κB 是强大的肿瘤促进剂 与几乎所有人类癌症有关，但鉴于其生理重要性，目前无法在临床上作为目标。此外，这些研究在 NF-κB 和癌症方面都有概念和技术创新， 因为它们为研究 NF-κB 在癌症和生理学中的差异调节和作用开辟了新途径， 并可能带来新的临床可行的方法来选择性地靶向致病性 NF-κB 进行癌症治疗。