Role of SHOX2 in breast tumor progression and metastasis

SHOX2在乳腺肿瘤进展和转移中的作用

基本信息

批准号：
8747351
负责人：
SHUANG HUANG
金额：
$ 31.37万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-02 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8747351
关键词：
Affect Binding Binding Sites Bioinformatics Breast Breast Cancer Cell Cancer Patient Cells Cessation of life Characteristics Clinical Complex Distant Epigenetic Process Epithelial Equilibrium Evaluation Event Family Feedback Foundations Genetic Transcription Goals Growth Factor Histone H3 Homeobox In Vitro Invaded Knowledge Lysine Malignant Neoplasms Mammary Neoplasms Mesenchymal Messenger RNA MicroRNAs Modality Neoplasm Metastasis Organ Outcome Play Primary Neoplasm Process Recruitment Activity Recurrence Regulation Repression Right-On Role Signal Pathway Signal Transduction Testing Therapeutic Time Transcription Coactivator Untranslated Regions Work Xenograft Model anti-cancer therapeutic base breast tumorigenesis cancer cell cancer stem cell cellular targeting cytokine epithelial to mesenchymal transition in vivo innovation malignant breast neoplasm neoplastic cell novel overexpression promoter public health relevance receptor stem cell population success trait transcription factor tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The metastatic spread of epithelial cancer cells from the primary tumor to distant organs necessitates tumor cells to gain mesenchymal characteristics and to lose epithelial features, a phenomenon known as the epithelial-mesenchymal transition (EMT). Various factors, including cytokines/growth factors in tumor microenvironment, transcription factors belonging to homeobox (HOX) super-family and microRNAs (miRNAs), can induce EMT. In a systematic evaluation of miRNA:mRNA pair important for breast cancer cell EMT, we found that miR-375 is present in high abundance in epithelial-like cells but very low in mesenchymal-like ones. Among miR-375's putative targets, SHOX2 is expressed at high level in mesenchymal-like breast cancer cells but lowly expressed in epithelial-like ones. To investigate the role of miR-375:SHOX2 pair in breast cancer cell EMT, we found that enforced miR-375 expression is sufficient to abrogate EMT traits in mesenchymal-like breast cancer cells while SHOX2 overexpression can potently induce EMT in epithelial-like cells. We discovered a double negative miR-375/SHOX2 feedback loop in which miR-375 suppresses endogenous SHOX2 expression by directly targeting SHOX2's 3'-UTR whereas SHOX2 represses miR-375 transcription through the action of Lysine (K)-Specific Demethylase 5B (KDM5B). In addition, SHOX2 also promotes TGF¿ receptor I (T¿RI) transcription, an event also capable of promoting EMT. Based on these findings, we formed our central hypothesis: miR-375/SHOX2 pair is dynamically involved in breast cancer cell EMT. Because of the well-recognized importance of EMT in breast malignancies, our goal of this proposal is to elucidate the basis of miR-375/SHOX2 feedback regulatory loop and the mechanisms underlying the dual action of SHOX2 in EMT induction. Moreover, we also intend to develop a therapeutic strategy through targeting events critical for SHOX2-induced EMT. Three specific aims are proposed in this application: 1) Understand how SHOX2 suppresses miR-375 expression in breast cancer cells; 2) Define mechanisms underlying SHOX2/miR-375 regulation of EMT in breast cancer cells; and 3) Determine the role of SHOX2 in breast tumorigenesis. The success of this application will have important impact in providing knowledge on both understanding EMT and building foundation for novel anti-cancer therapeutic modality.

描述（由申请人提供）：上皮癌细胞从原发肿瘤到远处器官的转移性扩散需要肿瘤细胞获得间质特征并失去上皮特征，这种现象被称为上皮间质转化（EMT）。包括肿瘤微环境中的细胞因子/生长因子、属于同源框（HOX）超家族的转录因子和微小RNA（miRNA），可以诱导EMT。对乳腺癌细胞 EMT 重要的 miRNA:mRNA 对进行系统评估，我们发现 miR-375 在上皮样细胞中含量很高，但在间质样细胞中含量很低。在 miR-375 的假定靶标中，SHOX2 表达。 miR-375:SHOX2 在间质样乳腺癌细胞中高表达，但在上皮样乳腺癌细胞中低表达，以研究 miR-375:SHOX2 对在乳腺癌细胞中的作用。 EMT，我们发现强制 miR-375 表达足以消除间充质样乳腺癌细胞中的 EMT 特征，而 SHOX2 过表达可以有效诱导上皮样细胞中的 EMT，我们发现了一个双负 miR-375/SHOX2 反馈环路。 miR-375 通过直接靶向 SHOX2 的 3'-UTR 来抑制内源性 SHOX2 表达，而 SHOX2 通过赖氨酸 (K) 特异性脱甲基酶 5B (KDM5B) 的作用此外，SHOX2 还促进 TGF¿受体 I (T¿RI) 转录也是能够促进 EMT 的事件，基于这些发现，我们形成了我们的中心假设：miR-375/SHOX2 对动态地参与乳腺癌细胞 EMT。为了了解乳腺恶性肿瘤中 EMT 的作用，我们本提案的目标是阐明 miR-375/SHOX2 反馈调节环路的基础以及 SHOX2 在 EMT 诱导中双重作用的机制。该申请还打算通过针对 SHOX2 诱导的 EMT 关键事件来制定治疗策略：1）了解 SHOX2 如何抑制乳腺癌细胞中的 miR-375 表达；2）定义 SHOX2/miR- 的潜在机制。第375章乳腺癌细胞中EMT的调节；3)确定SHOX2在乳腺肿瘤发生中的作用新型抗癌治疗方式。