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 这项研究的总体目标是了解Twist 1在皮肤鳞状细胞中的作用。 并开发靶向Twist 1的新方法来预防和治疗这种癌症。 重大疾病。Twist 1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。在我们实验室以前的研究中，我们发现 Twist 1在TPA促进皮肤肿瘤形成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外，在皮肤癌发生过程的早期也有作用， 转移这些早期的研究表明，Twist 1调节G1-S期细胞周期蛋白的水平。 此外，Twist 1被证明可以调节p53和p21的功能。到目前为止，Twist 1对紫外线的影响 皮肤癌的发生还没有研究，因此证明Twist 1也起作用是很重要的。 在紫外线皮肤致癌作用中起关键作用。在新的初步实验中，我们发现， 角质形成细胞导致角质形成细胞分化。此外，Twist 1在基底角质形成细胞中的缺失， 小鼠表皮在体内导致肿胀区角质形成干细胞（KSC）的变化，包括 KSC位于隆突区之外。这些发现表明，Twist 1可能在调节 角化细胞分化和KSC稳态所需。在额外的初步实验中，我们有 发现在Twist 1缺陷的角质形成细胞中，Ovol 1表达显著上调，这可能是 来推动差异化。此外，我们还发现，骆驼蓬碱，一种天然化合物， 据报道，通过促进Twist 1的降解来抑制Twist 1，诱导角质形成细胞的分化并上调 Ovol 1的表达与Twist 1 KO小鼠表皮相似。在本提案中，我们将测试 假设Twist 1在UV诱导的cSCC中起着关键作用，通过维持 表皮角质形成细胞，包括KSC的增殖和分化，通过调节 Ovol 1和以Twist 1为靶点的蛋白能有效抑制紫外线诱导的cSCC。具体目标如下： 进一步研究Twist 1在调节角质形成细胞和KSC增殖和分化中的作用; ii） 检查角质形成细胞特异性缺失Twist 1对UV诱导的皮肤致癌作用的影响; iii） 确定Ovol 1作为Twist 1的下游效应物在调节人乳腺癌细胞增殖和分化中的作用。 iv）进一步评估Harmine（一种新型Twist 1抑制剂）预防UV-1的能力。 诱发皮肤癌。完成拟议的研究将进一步阐明Twist 1在以下方面的作用： 角质形成细胞和KSC的增殖和分化及其在cSCC发生中的作用，尤其是在早期 皮肤肿瘤的发展阶段。将Twist 1鉴定为皮肤癌发展的关键早期参与者， 为预防和治疗cSCC提供了新的方法。新型预防药物的开发 和/或治疗，如本赠款申请中提出的，可以导致这些药物快速转化为临床。