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，以复发而臭名昭著，导致生存率较低。 癌细胞的侵袭是复发和进展的关键，强调了研究的重要性 侵袭机制，以提高患者的生存。我们最近发现了一种机制，在这种机制中，鳞癌 联合选择邻近的非癌上皮，称为癌症相关角质形成细胞(CAKs)，以增强 侧方侵犯，这与复发有关。恶性脑肿瘤1(DMBT1)的缺失 抑制子，在鳞癌中下调，促进侧向侵袭和卫星病变的形成。在反馈中 循环，干细胞分泌的转化生长因子-β(转化生长因子)抑制CAK中的DMBT1；这导致CAK 释放细胞因子，增强肿瘤细胞对肿瘤的侵袭能力。建议的目标是 研究目的是了解转化生长因子是如何抑制CAK中DMBT1的，以及为什么会这样做。有趣的是，DMBT1也是 一种抗微生物蛋白；初步数据显示，DMBT1在CAK中的下调增加了易感性 牙周病的关键致病菌牙龈卟啉单胞菌。两者之间有很强的相关性 口腔微生物群中的鳞状细胞癌和生物失调。多项研究表明，牙龈假单胞菌可增强鳞状细胞癌 侵袭性，但没有人研究牙龈假单胞菌通过CAK增强SCC侵袭性的能力。正常 感染牙龈假单胞菌的角质形成细胞分泌促炎细胞因子。总体假设是 SCC通过转化生长因子抑制CAK中的DMBT1促进细菌进入CAK，从而 促进细胞因子的释放，促进鳞状细胞癌的侵袭。为了验证这一假设，我们提出了两个目标： 目的#1：描述转化生长因子抑制CAK中DMBT1的分子机制；目的#2： 研究CAK中DMBT1抑制对细菌进入、前侵袭性细胞因子释放的影响 鳞状细胞癌侵袭。为了了解DMBT1在CAK中的抑制机制，我们将在遗传学和 细胞系中的药理学方法。了解DMBT1抑制在急性冠脉综合征中的意义 ，我们将使用高通量蛋白质组学来研究CAK的分泌组，以及遗传和 利用体外和体内模型确定这些细胞因子在侵袭中的作用的药理学方法， 包括Dmbt1-/-小鼠。总体而言，本项目将调查SCC增选CAK以 促进细胞因子的释放，增强肿瘤的侵袭性；这可以提供治疗靶点，以防止 鳞状细胞癌复发，提高生存率。