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: 10696941
• 负责人: Erika Bunnine Danella
• 金额: $ 5.35万
• 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/10696941
• 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 Cells; Epithelium; Feedback; Genetic; Genetic Transcription; Goals; Human; Immune; In Vitro; Inflammatory; Interleukin-6; Invaded; Lateral; Lesion; Malignant Epithelial Cell; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Microbe; Modeling; Molecular; Mus; Oral; Oral health; Patients; Periodontal Diseases; Porphyromonas gingivalis; Predisposition; Proliferating; Promoter Regions; Protein Secretion; Proteins; Proteomics; Quantitative Reverse Transcriptase PCR; Recurrence; Research; Role; Saliva; Salivary Glands; Signal Pathway; Signal Transduction; Squamous cell carcinoma; Testing; Transfection; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Cell Invasion; Tumor Suppressor Proteins; Validation; Western Blotting; With laterality; 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; pharmacologic; 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.

项目总结/摘要 鳞状细胞癌（SCC）是最常见的口腔癌，众所周知会复发，导致生存率低下。 癌细胞的侵袭对于复发和进展至关重要，强调了研究的重要性。 以提高患者的生存率。我们最近发现了一种机制， 选择邻近的非癌上皮，称为癌症相关角质形成细胞（CAK），以增强 外侧侵犯，这与复发有关。恶性脑肿瘤1（DMBT 1）， 在SCC中下调，以促进侧向侵袭和卫星病变的形成。以反馈 环，SCC分泌的转化生长因子β（TGF β）抑制CAKs中的DMBT 1;这导致CAKs 释放增强肿瘤细胞远离肿瘤块的侵袭的细胞因子。建议的目标 这项研究的目的是了解TGF β 1如何抑制CAKs中的DMBT 1以及为什么会这样。有趣的是，DMBT 1也是 一种抗微生物蛋白;初步数据显示CAKs中DMBT 1的下调增加了易感性 牙龈卟啉单胞菌，牙周病的关键病原体。之间存在很强的相关性 口腔微生物群中的SCC和生态失调。多项研究表明，牙龈卟啉单胞菌可增强SCC 但是没有人检测牙龈卟啉单胞菌通过CAK增强SCC侵袭的能力。正常 感染牙龈卟啉单胞菌的角质形成细胞分泌促炎细胞因子。总的假设是， SCC介导的通过TGF β 1抑制CAKs中的DMBT 1促进细菌进入CAKs，从而 促进细胞因子的释放，促进SCC的侵袭。为了验证这一假设，我们提出了两个目标： 目的#1：表征TGF β 1抑制CAK中DMBT 1的分子机制;以及目的#2： 研究CAK中DMBT 1抑制对细菌进入、促侵袭细胞因子释放和 SCC入侵。为了了解CAKs中DMBT 1抑制的机制，我们将使用遗传和 细胞系的药理学方法。为了了解CAKs中DMBT 1抑制的意义， SCC的侵袭，我们将使用高通量蛋白质组学研究CAKs的分泌组，以及基因和 使用体外和体内模型建立这些细胞因子在侵袭中的作用的药理学方法， 包括Dmbt 1-/-小鼠。总的来说，本项目将调查SCC增选CAK的机制， 促进细胞因子的释放，增强肿瘤侵袭;这可以提供治疗靶点，以防止 SCC复发，提高生存率。