The Role of Sox11 in Skin Squamous Cell Carcinoma

Sox11 在皮肤鳞状细胞癌中的作用

• 批准号: 8957180
• 负责人: Hoang Nguyen
• 金额: $ 20.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-11 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8957180
• 关键词: Ablation; Adult; Affect; Apoptosis; Basal cell carcinoma; Boxing; Cell Fate Control; Cell physiology; Characteristics; Chemicals; Data; Development; Diagnostic; Disease; Embryo; Epidermis; Epithelial; Family; Genes; Genetic; Human; Incidence; Knockout Mice; Knowledge; Light; Malignant - descriptor; Malignant Neoplasms; Mantle Cell Lymphoma; Pattern; Phenocopy; Play; Premalignant; Process; Protocols documentation; Regulation; Role; Skin; Skin Cancer; Squamous cell carcinoma; Testing; Tetanus Helper Peptide; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Mice; Tumorigenicity; Up-Regulation; base; cancer type; chemical carcinogenesis; dimethylbenzanthracene; embryonic stem cell; improved; in vivo; insight; malignant breast neoplasm; member; migration; mouse model; novel; overexpression; programs; public health relevance; research study; senescence; skin squamous cell carcinoma; stem cell fate; tool; transcription factor; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): Embryonic stem cell signature genes are often activated in multiple types of aggressive tumors, suggesting that the activation of embryonic genes might contribute to the poorly differentiated characteristics of tumors. Squamous cell carcinoma (SCC) of the skin is the second most common skin cancer, with 700,000 new cases every year in the U.S. Although its incidence is lower than that of basal cell carcinoma, its metastatic potential is much greater. Despite the high incidence of skin SCC, our knowledge of the key components and mechanisms underlying its development and progression is still quite limited. Moreover, it is not known whether the embryonic gene program is reactivated in skin SCC as it is in other aggressive types of tumors. It is therefore essential to identify the instrumental components in skin SCC in order to uncover novel targets for improved diagnostic and/or therapeutic intervention. Sox11 is overexpressed in a variety of tumors, but its exact role in cancer is still unclear. Sox11 is a member of the SRY-related high-mobility-group box (Sox) family of transcription factors, which control cell fate and differentiation in a variety of tissue. In skin, Sox11 is expressed in embryonic epidermis; it is absent in adult tissue but is reactivated in skin SCC. Our preliminary studies show that Sox11 overexpression in skin induces hyperproliferation, suppresses differentiation and increases the incidence of tumors. We find that Sox11 overexpression induces the expression of Tcf3, a transcription factor that plays an important role in the regulation of epidermal stem cell fate. We also find that Sox11 overexpressing skins phenocopy Tcf3 overexpressing skins and that overexpression of Tcf3 promotes tumor growth and progression in a mouse model of skin SCC. Based on these data, we hypothesize that overexpression of Sox11 contributes to tumorigenesis through its upregulation of Tcf3. To test our hypothesis and elucidate the role of Sox11 in skin SCC, we propose the following aims: Aim 1: To determine the role of Sox11 in mouse model of skin SCC. To determine how the dysregulation of Sox11 expression contributes to tumor formation, we will employ the DMBA/TPA chemical carcinogenesis protocol on tet-inducible Sox11 transgenic mice and Sox11 conditional knockout mice. Aim 2: To determine the mechanism underlying Sox11's tumorigenic role. To test our hypothesis that Sox11 promotes tumorigenesis through Tcf3 up-regulation, we will evaluate the tumorigenicity of Sox11 overexpression in a Tcf3-deficient background. In parallel, we will identify the cellular processes regulated by Sox11 and determine the extent to which Sox11 affects these processes through its regulation of Tcf3.

 描述（由申请人提供）：胚胎干细胞特征基因通常在多种类型的侵袭性肿瘤中被激活，表明胚胎基因的激活可能导致肿瘤的低分化特征。皮肤鳞状细胞癌（SCC）是第二常见的皮肤癌，在美国每年有70万例新发病例，虽然其发病率低于基底细胞癌，但其转移潜力要大得多。尽管皮肤鳞状细胞癌的发病率很高，但我们对其发生和发展的关键成分和机制的了解仍然非常有限。此外，目前还不知道胚胎基因程序是否在皮肤SCC中重新激活，因为它是在其他侵袭性类型的肿瘤。因此，它是必不可少的，以确定皮肤SCC中的工具组件，以发现新的目标，以改善诊断和/或治疗干预。Sox 11在多种肿瘤中过度表达，但其在癌症中的确切作用仍不清楚。Sox 11是SRY相关的高迁移率族盒（Sox）转录因子家族的成员，其控制多种组织中的细胞命运和分化。在皮肤中，Sox 11在胚胎表皮中表达;它在成人组织中不存在，但在成年组织中被重新激活。 皮肤SCC我们的初步研究表明，Sox 11在皮肤中的过表达诱导过度增殖，抑制分化，并增加肿瘤的发病率。我们发现Sox 11过表达会诱导Tcf 3的表达，Tcf 3是一种在调节表皮干细胞命运中发挥重要作用的转录因子。我们还发现，Sox 11过表达的皮肤表型Tcf 3过表达的皮肤和Tcf 3的过表达促进肿瘤的生长和发展，在小鼠模型的皮肤SCC。基于这些数据，我们假设Sox 11的过度表达通过上调Tcf 3而促进肿瘤发生。为了验证我们的假设并阐明Sox 11在皮肤SCC中的作用，我们提出以下目的：目的1：确定Sox 11在皮肤SCC小鼠模型中的作用。为了确定Sox 11表达的失调如何导致肿瘤形成，我们将采用DMBA/TPA化学致癌方案对tet诱导的Sox 11转基因小鼠和Sox 11条件性敲除小鼠进行研究。目的2：探讨Sox 11的致瘤机制。为了验证我们的假设，即Sox 11通过Tcf 3上调促进肿瘤发生，我们将评估在Tcf 3缺陷背景下Sox 11过表达的致瘤性。同时，我们将确定由Sox 11调节的细胞过程，并确定Sox 11通过调节Tcf 3影响这些过程的程度。