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

• 批准号: 10424568
• 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
• 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/10424568
• 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; Epithelial; Equilibrium; Exposure to; G1 Phase; Genes; Genetic; Goals; Harmine; Immunofluorescence Immunologic; Incidence; Knockout Mice; Laboratories; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Mesenchymal; Messenger RNA; Modeling; Mus; Neoplasm Metastasis; Play; Prevention; Prevention approach; Process; Proliferation Marker; Proteins; Protocols documentation; Regulation; Reporting; Research; Role; 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; base; 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

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.

项目摘要 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（CSCC），并开发针对扭曲1的新方法来预防和治疗这一点 重要疾病。 Twist1是参与上皮 - 间质转变和癌症的转录因子 许多上皮癌中的进展和转移。在我们实验室的先前研究中，我们发现 在TPA促进皮肤肿瘤的过程中，需要这种扭曲1才能增殖。 除了在癌症进展中的作用和 转移。这些较早的研究表明，Twist1调节G1-S相细胞周期蛋白的水平。 此外，扭曲1被证明可以调节p53和p21的功能。迄今为止，Twist1对UV的影响 尚未研究皮肤致癌作用，因此重要的是要证明Twist1还发挥作用 在紫外皮肤致癌中的关键作用。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，在基底角质形成细胞中删除Twist1 小鼠表皮体内体内导致隆起 - 区域角质形成干细胞（KSC）的变化，包括迁移 KSC从凸出区域出来。这些发现表明Twist1可能在调节中起重要作用 角质形成细胞分化，是KSC稳态所必需的。在其他初步实验中，我们有 发现在Twist1缺乏角质形成细胞中，Ovol1表达显着上调，可能是负责的 用于驱动差异。此外，我们还发现Harmine，一种天然存在的化合物 据报道，通过促进其降解来抑制Twist1，诱导角质形成细胞的分化并上调 OVOL1的方式与Twist1 Ko小鼠表皮相似。在此提案中，我们将测试 Twist1的假设通过保持在UV诱导的CSCC中起关键作用。 表皮角质形成细胞的增殖和分化，包括KSC通过调节 ovol1和靶向扭曲1将有效抑制紫外线诱导的CSCC。具体目的如下：i） 进一步研究Twist1在调节角质形成细胞和KSC的扩散和分化中的作用； ii） 检查角质形成细胞特异性扭曲1对紫外线诱导的皮肤致癌作用的影响； iii） 确定ovol1作为扭曲1的下游效应子在调节增殖和分化中的作用 角质形成细胞和KSCSAND IV）进一步评估了一种新型Twist1抑制剂Harmine的能力，以防止紫外线 诱导皮肤致癌。拟议研究的完成将进一步阐明扭曲1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，尤其是在早期 皮肤肿瘤发育的阶段。将Twist1识别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。开发新颖的预防代理商 和/或本授予申请中提出的治疗可能会导致此类药物快速转化为诊所。