Twist1 as a Target for Prevention and Treatment of Cutaneous Squamous Cell Carcinoma

Twist1作为预防和治疗皮肤鳞状细胞癌的靶点

基本信息

批准号：
10651792
负责人：
John DiGiovanni
金额：
$ 35.53万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651792
关键词：
Alkaloids Applications Grants Automobile Driving Basal cell carcinoma Biological Models Carcinoma Cell Culture Techniques Cell Cycle Proteins Cell Differentiation process Cessation of life Clinic Data Development Differentiation Antigens Disease Epidermis Epithelium Equilibrium Exposure to G1 Phase Genes Genetic Goals Harmine Immunofluorescence Immunologic Incidence Knockout Mice Laboratories LoxP-flanked allele Malignant Epithelial Cell Malignant Neoplasms Mesenchymal Messenger RNA Modeling Mus Natural Compound Neoplasm Metastasis Play Prevention Prevention approach Process Proliferating Proliferation Marker Proteins Protocols documentation Regulation Reporting Research Role S phase Skin Cancer Skin Carcinogenesis Skin Carcinoma Skin Neoplasms Squamous cell carcinoma Study Section TP53 gene Testing Transgenic Mice Translations Tumor Promotion UV induced Ultraviolet B Radiation cell behavior design experimental study in vivo in vivo Model inhibitor keratinocyte keratinocyte differentiation knock-down migration mouse model novel novel strategies overexpression prevent progenitor response skin squamous cell carcinoma stem stem cell homeostasis stem cell proliferation stem cells stemness transcription factor tumor tumor progression

项目摘要

PROJECT SUMMARY The overall goal of the proposed research is to understand the role of Twist1 in cutaneous squamous cell carcinoma (cSCC) and to develop novel approaches for targeting Twist1 for prevention and treatment of this important disease. Twist1 is a transcription factor involved in epithelial-mesenchymal transition and cancer progression and metastasis in a number of epithelial cancers. In previous studies from our laboratory, we found that Twist1 was required for proliferation of keratinocytes during the process of skin tumor promotion by TPA suggesting a role early in the process of skin carcinogenesis in addition to its role in cancer progression and metastasis. These earlier studies showed that Twist1 regulated levels of G1-S-phase cell cycle proteins. Furthermore, Twist1 was shown to regulate the function of p53 and p21. To date, the impact of Twist1 on UV skin carcinogenesis has not been studied and therefore it is important to demonstrate that Twist1 also plays critical role in UV skin carcinogenesis. In new preliminary experiments, we have found that deletion of Twist1 in keratinocytes leads to keratinocyte differentiation. Furthermore, deletion of Twist1 in basal keratinocytes of mouse epidermis in vivo leads to changes in bulge-region keratinocyte stem cells (KSCs), including migration of KSCs out of the bulge region. These findings suggest that Twist1 may play an important role in regulating keratinocyte differentiation and be required for KSC homeostasis. In additional preliminary experiments, we have found that Ovol1 expression is significantly upregulated in Twist1 deficient keratinocytes and may be responsible for driving differentiation. Furthermore, we have also found that Harmine, a naturally occurring compound reported to inhibit Twist1 by facilitating its degradation, induces differentiation in keratinocytes and upregulates Ovol1 in a manner similar to that seen in epidermis of Twist1 KO mice. In this proposal, we will test the hypothesis that Twist1 plays a critical role in UV-induced cSCC by maintaining the balance between proliferation and differentiation of epidermal keratinocytes, including KSCs via regulation of the levels of Ovol1 and that targeting Twist1 will effectively inhibit UV-induced cSCC. The specific aims are as follows: i) To further examine the role of Twist1 in regulating proliferation and differentiation of keratinocytes and KSCs; ii) To examine the impact of keratinocyte specific deletion of Twist1 on UV-induced skin carcinogenesis; iii) Determine the role of Ovol1 as a downstream effector of Twist1 in regulating proliferation and differentiation of keratinocytes and KSCsand iv) Further evaluate the ability of Harmine, a novel Twist1 inhibitor, to prevent UV- induced skin carcinogenesis. Completion of the proposed studies will further elucidate the role of Twist1 in keratinocyte and KSC proliferation and differentiation and its role in development of cSCC, especially in the early stages of skin tumor development. Identification of Twist1 as a key early player in skin cancer development could lead to novel approaches for the prevention and treatment of cSCC. Development of novel agents for prevention and/or treatment as proposed in this grant application could lead to rapid translation of such agents into the clinic.

项目概要拟议研究的总体目标是了解 Twist1 在皮肤鳞状细胞中的作用癌症 (cSCC) 并开发针对 Twist1 的新方法来预防和治疗这种癌症重要的疾病。 Twist1 是一种参与上皮间质转化和癌症的转录因子许多上皮癌的进展和转移。在我们实验室之前的研究中，我们发现 Twist1在TPA促进皮肤肿瘤的过程中是角质形成细胞增殖所必需的表明除了在癌症进展中的作用之外，它还在皮肤癌发生的早期过程中发挥作用，转移。这些早期研究表明 Twist1 调节 G1-S 期细胞周期蛋白的水平。此外，Twist1 可调节 p53 和 p21 的功能。迄今为止，Twist1 对紫外线的影响皮肤癌的发生机制尚未被研究，因此证明 Twist1 也发挥作用非常重要紫外线在皮肤癌发生中起关键作用。在新的初步实验中，我们发现 Twist1 的删除角质形成细胞导致角质形成细胞分化。此外，基底角质形成细胞中 Twist1 的缺失小鼠表皮在体内导致凸起区域角质形成细胞干细胞（KSC）发生变化，包括迁移 KSC 脱离凸起区域。这些发现表明 Twist1 可能在调节中发挥重要作用角质形成细胞分化并且是 KSC 稳态所必需的。在额外的初步实验中，我们有发现 Twist1 缺陷的角质形成细胞中 Ovol1 表达显着上调，这可能是其原因推动差异化。此外，我们还发现了 Harmine，一种天然存在的化合物据报道可通过促进 Twist1 降解来抑制 Twist1，诱导角质形成细胞分化并上调 Ovol1 的作用方式与 Twist1 KO 小鼠表皮中观察到的类似。在本提案中，我们将测试假设 Twist1 通过维持之间的平衡在紫外线诱导的 cSCC 中发挥关键作用通过调节表皮角质形成细胞（包括 KSC）的水平来增殖和分化 Ovol1 和靶向 Twist1 的药物将有效抑制紫外线诱导的 cSCC。具体目标如下： i) 进一步研究Twist1在调节角质形成细胞和KSC增殖和分化中的作用；二）研究角质形成细胞特异性删除 Twist1 对紫外线诱导的皮肤癌发生的影响；三）确定 Ovol1 作为 Twist1 下游效应子在调节细胞增殖和分化中的作用角质形成细胞和 KSCs 和 iv) 进一步评估 Harmine（一种新型 Twist1 抑制剂）预防 UV- 诱发皮肤癌。拟议研究的完成将进一步阐明 Twist1 在角质形成细胞和 KSC 的增殖和分化及其在 cSCC 发展中的作用，特别是在早期皮肤肿瘤发展的阶段。鉴定 Twist1 作为皮肤癌发展的关键早期参与者可能导致预防和治疗 cSCC 的新方法。开发新型预防剂本拨款申请中提出的和/或治疗可能会导致此类药物快速转化为临床。