Roles of p63 in regulation of miRNA and LincRNA targets in metastatic cancer

p63 在转移性癌症中 miRNA 和 LincRNA 靶标调节中的作用

• 批准号: 8461599
• 负责人: Elsa R Flores
• 金额: $ 45.74万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461599
• 关键词: Address; Alleles; Apoptosis; Applications Grants; Biogenesis; Brain; Breast Adenocarcinoma; Carcinoma; Cell Maintenance; Cells; DNA Damage; Data; Development; Disseminated Malignant Neoplasm; Distant Metastasis; Enzymes; Epidermis; Family; Family member; Financial compensation; Functional RNA; Genes; Goals; Human; Knockout Mice; Laboratories; Length; Lung Adenocarcinoma; Malignant Neoplasms; Metastasis Suppression; Metastatic Carcinoma; Metastatic Skin Cancer; Metastatic Squamous Cell Carcinoma; MicroRNAs; Morphogenesis; Mus; Nature; Neoplasm Metastasis; Pathway interactions; Patients; Play; Positioning Attribute; Process; Protein Isoforms; Publishing; Regulation; Research; Role; Sampling; Skin; Skin Cancer; Squamous cell carcinoma; Stem cells; System; Therapeutic Intervention; Transactivation; Transcriptional Regulation; Tumor Suppression; cancer therapy; human DICER1 protein; improved; in vivo; innovation; mortality; mouse model; mutant; novel; response; skin squamous cell carcinoma; stem; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Mortality in cancer is most often due to the development of distant metastases for which almost no effective systemic treatments exist. The study of genes relevant for the regulation of metastasis in vivo is therefore of great importance. The functions of p63, a p53 family member, are beginning to be understood in contexts in which p53 function has been well established, including apoptosis and tumor suppression (Su et al., Nature 2010) as well as in other roles such as metastasis (Su et al., Nature 2010), skin development, and stem cell maintenance (Su et al., Cell Stem Cell 2009). The complexity of p63 function is due in part to the existence of multiple isoforms that previously could not be studied independently. Full length TA isoforms of p63 contain a transactivation domain, structurally and functionally resembling p53, whereas the ?N isoforms of p63, while also possessing transactivation activity, antagonize the activities of p53 and the TA isoforms of p63 and p73, the other p53 family member. Interestingly, mutant p53, present in a wide variety of human cancers, has been shown to interact with p63 isoforms and inactivate their function. By generating and studying mice with isoform-specific null alleles of p63, the TAp63-/- and ?Np63-/- mice, we have shown that these genes have distinct roles in suppression of tumorigenesis and metastasis. TAp63-/- mice are highly susceptible to spontaneous metastatic tumors, and TAp63 potently suppresses tumor metastasis by direct coordinate transcriptional regulation of Dicer and several miRNAs (Su et al., Nature 2010). In addition, we have extended these findings to multiple human tumor types including squamous cell carcinoma, lung adenocarcinoma, and breast adenocarcinoma, indicating this function of TAp63 is widely important. We have also shown that ?Np63 can suppress invasion and transcriptionally regulates DGCR8, another critically important enzyme necessary for miRNA processing. We hypothesize that TAp63 and ?Np63 regulate distinct miRNAs in different cellular compartments to suppress tumorigenesis and metastasis and to engage the DNA damage response. We will address our hypothesis by proposing the following specific aims: Specific Aim 1: To understand the mechanistic regulation of miRNA and LincRNA targets by p63 isoforms in the cell of origin of carcinomas (epidermal cells). Specific Aim 2: To understand the mechanistic regulation of miRNAs and LincRNAs by p63 isoforms in stem cells of skin cancer and metastasis. Specific Aim 3: To understand the roles of miRNAs and LincRNAs regulated by p63 isoforms in the DNA damage response and p53 compensation.

描述（由申请人提供）：癌症的死亡率通常是由于远处转移的发展，对此几乎没有有效的全身治疗。因此，研究与体内转移调控相关的基因具有重要意义。p53家族成员p63的功能开始在p53功能已经很好建立的背景下被理解，包括细胞凋亡和肿瘤抑制（Su et al.，Nature 2010）以及其他作用如转移（Su et al.，Nature 2010）、皮肤发育和干细胞维持（Su et al. Cell Stem Cell 2009）。p63功能的复杂性部分是由于以前无法独立研究的多种亚型的存在。全长TA异构体的p63含有一个反式激活结构域，结构和功能类似p53，而？p63的N亚型，同时也具有反式激活活性，拮抗p53和p63和p73的TA亚型的活性，p53家族的另一个成员。有趣的是，存在于多种人类癌症中的突变型p53已被证明与p63亚型相互作用并破坏其功能。 通过产生和研究小鼠的亚型特异性无效等位基因的p63，TAp 63-/-和？Np 63-/-小鼠中，我们已经表明这些基因在抑制肿瘤发生和转移中具有不同的作用。TAp 63-/-小鼠对自发转移性肿瘤高度易感，并且TAp 63通过Dicer和几种miRNA的直接协同转录调节而有效地抑制肿瘤转移（Su et al.，Nature 2010）。此外，我们已经将这些发现扩展到多种人类肿瘤类型，包括鳞状细胞癌，肺腺癌和乳腺癌，表明TAp 63的这种功能非常重要。我们也证明了这一点。Np 63可以抑制入侵并转录调节DGCR 8，这是miRNA加工所必需的另一种至关重要的酶。我们假设TAp 63和？Np 63在不同的细胞区室中调节不同的miRNA，以抑制肿瘤发生和转移，并参与DNA损伤反应。我们将通过提出以下具体目标来解决我们的假设：具体目标1：了解癌起源细胞（表皮细胞）中p63亚型对miRNA和LincRNA靶标的机制调节。具体目标2：了解皮肤癌干细胞和转移灶中p63亚型对miRNAs和LincRNAs的调控机制。具体目标3：了解p63亚型调控的miRNAs和LincRNAs在DNA损伤反应和p53补偿中的作用。