Exploring the Role of DMBT1 Suppression in Invasion of Oral Cancer

探索 DMBT1 抑制在口腔癌侵袭中的作用

• 批准号: 10462188
• 负责人: Erika Bunnine Danella
• 金额: $ 5.26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462188
• 关键词: Aftercare; Bacteria; Bacterial Infections; Binding; Biological; Biological Assay; Cancer Etiology; Cell Line; Cells; Chemicals; Data; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Feedback; Genetic; Genetic Transcription; Goals; Human; Immune; In Vitro; Inflammatory; Interleukin-6; Invaded; Lateral; Lead; Lesion; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of salivary gland; Mass Spectrum Analysis; Mediating; Microbe; Modeling; Molecular; Mus; Oral; Oral health; Patients; Periodontal Diseases; Pharmacology; Porphyromonas gingivalis; Predisposition; Proliferating; Promoter Regions; Proteins; Proteomics; Quantitative Reverse Transcriptase PCR; Recurrence; Research; Role; Saliva; Salivary Glands; Signal Pathway; Signal Transduction; Squamous cell carcinoma; Testing; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Cell Invasion; Tumor Suppressor Proteins; Validation; Western Blotting; activating transcription factor 3; antimicrobial; cancer cell; cell type; chemical carcinogenesis; cytokine; dysbiosis; enhancing factor; epidemiology study; glycoprotein 340; improved; in vitro Assay; in vivo Model; inhibitor; keratinocyte; malignant mouth neoplasm; microbiome; migration; mouth squamous cell carcinoma; neoplastic cell; new therapeutic target; oral microbiome; oral pathogen; pathogen; prevent; recruit; release factor; response; therapeutic target; transcription factor; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Squamous cell carcinoma (SCC), the most common oral cancer, notoriously recurs, leading to poor survival. Invasion of cancer cells is essential for recurrence and progression, emphasizing the importance of investigating mechanisms of invasion in order to improve patient survival. We recently identified a mechanism in which SCC co-opts adjacent non-cancerous epithelium, referred to as cancer-associated keratinocytes (CAKs), to enhance lateral invasion, which was associated with recurrence. Deleted in malignant brain tumors 1 (DMBT1), a tumor suppressor, is downregulated in SCC to promote lateral invasion and formation of satellite lesions. In a feedback loop, SCC-secreted transforming growth factor-beta (TGF) suppresses DMBT1 in CAKs; this causes CAKs to release cytokines that enhance invasion of tumor cells away from the tumor bulk. The objective of the proposed study is to understand how TGF suppresses DMBT1 in CAKs and why it does so. Interestingly, DMBT1 is also an anti-microbial protein; preliminary data show that downregulation of DMBT1 in CAKs increases susceptibility to Porphyromonas gingivalis, a keystone pathogen in periodontal disease. There is a strong correlation between SCC and dysbiosis in the oral microbiome. Multiple studies have shown that P. gingivalis enhances SCC invasion, but none have examined the ability of P. gingivalis to enhance SCC invasion via CAKs. Normal keratinocytes infected with P. gingivalis secrete pro-inflammatory cytokines. The overall hypothesis is that SCC-mediated suppression of DMBT1 in CAKs via TGF facilitates bacterial entry into CAKs, thereby enhancing release of cytokines that promote invasion of SCC. To test this hypothesis, we propose two aims: Aim #1: Characterize the molecular mechanism by which TGF suppresses DMBT1 in CAKs; and Aim #2: Investigate the impact of DMBT1 suppression in CAKs on bacterial entry, release of pro-invasive cytokines, and SCC invasion. To understand the mechanism of DMBT1 suppression in CAKs, we will use in genetic and pharmacological approaches in cell lines. To understand the significance of DMBT1 suppression in CAKs on SCC invasion, we will use high-throughput proteomics to investigate the secretome of CAKs, and genetic and pharmacologic approaches to establish the role of these cytokines in invasion using in in vitro and in vivo models, including Dmbt1-/- mice. Overall, this project will investigate the mechanism by which SCC co-opts CAKs to promote the release of cytokines that enhance tumor invasion; this could provide therapeutic targets to prevent SCC recurrence and improve survival.

项目摘要/摘要 鳞状细胞癌（SCC）是最常见的口腔癌，众所周知，导致生存率差。 癌细胞的侵袭对于复发和进展至关重要，强调研究的重要性 入侵机制以改善患者的生存。我们最近确定了一种机制 相邻的非癌性上皮，称为癌症相关角质形成细胞（CAKS），以增强 横向入侵与复发有关。在恶性脑肿瘤1（DMBT1）中删除，肿瘤 抑制剂在SCC中被下调，以促进卫星病变的横向浸润和形成。在反馈中 循环，SCC分泌转化的生长因子β（TGF）抑制了CAKS中的DMBT1；这导致caks 释放细胞因子，从而增强肿瘤细胞的侵袭远离肿瘤的大块。提议的目标 研究是了解TGF如何抑制CAKS中的DMBT1以及为什么这样做。有趣的是，DMBT1也是 抗微生物蛋白；初步数据表明，CAKS中DMBT1的下调会提高易感性 牙龈卟啉单胞菌，这是一种牙周疾病中的基石病原体。之间有很强的相关性 口服微生物组中的SCC和营养不良。多项研究表明，牙龈疟原虫增强了SCC 入侵，但没有人检查过牙龈疟原虫通过CAKS增强SCC入侵的能力。普通的 感染牙龈疟原虫的角质形成细胞分泌促炎细胞因子。总体假设是 SCC介导的DMBT1在CAKS中通过TGF促进细菌​​进入CAKS，从而促进 增强细胞因子促进SCC侵袭的释放。为了检验这一假设，我们提出了两个目标： 目标＃1：表征TGF抑制CAKS中DMBT1的分子机制；和目标＃2： 研究DMBT1抑制在CAKS中的影响对细菌的进入，促侵入性细胞因子的释放和 SCC入侵。为了了解CAKS中DMBT1抑制的机制，我们将用于遗传和 细胞系中的药理方法。了解DMBT1抑制在CAKS上的重要性 SCC入侵，我们将使用高通量蛋白质组学研究CAKS的分泌，遗传和 在体外和体内模型中使用这些细胞因子在侵袭中的作用的药理方法， 包括DMBT1 - / - 小鼠。总体而言，该项目将调查SCC选择CAKS的机制 促进细胞因子的释放，以增强肿瘤侵袭；这可以提供治疗目标以防止 SCC复发并提高生存率。