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.

项目概要/摘要 鳞状细胞癌 (SCC) 是最常见的口腔癌，众所周知，它会复发，导致生存率很低。 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 侵袭机制，以提高患者的生存率。我们最近发现了一种机制，其中 SCC 共同选择邻近的非癌性上皮，称为癌症相关角质形成细胞 (CAK)，以增强 侧向侵犯，这与复发相关。恶性脑肿瘤 1 (DMBT1) 中缺失的肿瘤 抑制因子在 SCC 中下调，促进侧向侵袭和卫星病变的形成。在反馈中 环，SCC 分泌的转化生长因子-β (TGF) 抑制 CAK 中的 DMBT1；这会导致 CAK 释放细胞因子，增强肿瘤细胞远离肿瘤体积的侵袭。拟议的目标 研究的目的是了解 TGF 如何抑制 CAK 中的 DMBT1 及其原因。有趣的是，DMBT1 也是 抗微生物蛋白；初步数据表明 CAK 中 DMBT1 的下调会增加易感性 牙龈卟啉单胞菌是牙周病的主要病原体。之间存在很强的相关性 口腔微生物群中的鳞状细胞癌和菌群失调。多项研究表明牙龈卟啉单胞菌可增强鳞状细胞癌 侵袭，但没有人检查牙龈卟啉单胞菌通过 CAK 增强鳞状细胞癌侵袭的能力。普通的 感染牙龈卟啉单胞菌的角质形成细胞分泌促炎细胞因子。总体假设是 SCC 介导的通过 TGF 对 CAK 中 DMBT1 的抑制有利于细菌进入 CAK，从而 增强细胞因子的释放，促进鳞状细胞癌的侵袭。为了检验这个假设，我们提出两个目标： 目标#1：表征 TGF 抑制 CAK 中 DMBT1 的分子机制；目标#2： 研究 CAK 中 DMBT1 抑制对细菌进入、促侵袭性细胞因子释放的影响，以及 SCC入侵。为了了解 CAK 中 DMBT1 抑制的机制，我们将在遗传和 细胞系中的药理学方法。了解 CAK 中 DMBT1 抑制的重要性 SCC侵袭，我们将利用高通量蛋白质组学研究CAK的分泌组，以及遗传和 使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，该项目将研究 SCC 增选 CAK 的机制 促进增强肿瘤侵袭的细胞因子的释放；这可以提供治疗目标来预防 SCC复发并提高生存率。