Role of miR-105 in breast cancer metastasis

miR-105在乳腺癌转移中的作用

• 批准号: 8394989
• 负责人: Shizhen Emily Wang
• 金额: $ 34.86万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394989
• 关键词: 3' Untranslated Regions; Anchorage-Independent Growth; Blood; Blood Circulation; Breast; Breast Cancer Cell; Cancer Patient; Cell Adhesion; Cell Line; Cell Polarity; Cell physiology; Cell-Cell Adhesion; Cells; Coculture Techniques; Communication; Development; Diagnostic Neoplasm Staging; Disease; Disease Progression; Distant Metastasis; Early Diagnosis; Early treatment; Encapsulated; Endothelial Cells; Environment; Epithelial; Epithelial Cells; Event; Evolution; Future; Gene Expression; Gene Targeting; Genes; Goals; Hematopoietic Neoplasms; Intervention; Kinetics; Malignant Neoplasms; Mammary gland; Mediating; MicroRNAs; Molecular; Mus; Neoplasm Metastasis; Pathway interactions; Patients; Permeability; Physiological; Play; Prevention; Primary Neoplasm; Process; Proteins; Resistance; Retroviridae; Role; Site; Staging; System; Tight Junctions; Tissues; Tube; Xenograft Model; cancer cell; cellular transduction; clinically significant; extracellular; in vivo; insight; malignant breast neoplasm; migration; mortality; mouse model; novel; novel strategies; novel therapeutics; overexpression; prevent; restoration; tumor; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) appear to play a role in mediating interactions between cancer cells and their hosting niche during cancer progression and metastasis. Our preliminary studies indicate that miR-105, whose levels in the circulation are associated with metastatic progression in early-stage breast cancer (BC) patients, is characteristically expressed and secreted by metastatic BC (MBC) cells. MiR-105 downregulates the tight junction protein ZO-1, for which reduced expression is associated with metastasis in BC patients. MiR-105 potently induces migration and proliferation in MBC cells, and can be transferred via MBC-secreted exosomes to normal epithelial and endothelial cells in the cancer niche, where it alters ZO-1 expression and the barrier function of these niche cells. In a mouse model established in our lab, MBC-secreted exosomes and miRNAs can be internalized by cells in various tissues, and can facilitate metastasis development. The goals of this study are to dissect the dual roles of miR-105 in regulating the metastatic potential of cancer cells and in destroying the epithelial and endothelial "barriers" in the cancer niche, and t explore novel therapeutic strategies that target miR-105-mediated pro-metastatic functions. In Aim 1, the effects of miR-105 on cancer cell adhesion, migration, invasion, proliferation and anchorage-independent growth, as well as the role of ZO-1 in mediating these effects, will be investigated. Additional miR-105-regulated genes will be identified and their role in mediating miR-105's effects will be determined. In Aim 2, the effects of cancer-secreted, exosome-transferred miR-105 on normal epithelial and endothelial niche cells will be determined, focusing on their "barrier" functions to restrict cancer cell invasion and metastasis. The magnitude and kinetics of miR-105-mediated barrier-destroying effects will be determined by co-culturing the epithelial and endothelial niche cells with MBC cells that secrete miR-105. In Aim 3, the in vivo effects of miR-105 on niche adaptation and BC metastasis will be determined using mouse xenograft models of BC. The anti-metastatic effect of miR- 105 intervention will be evaluated. These in-depth functional studies of cancer-secreted miRNAs that contribute to the co-evolution of the tumor-hosting environment will provide novel insights into the dynamic communication between cancer and host during disease progression. This study will also provide proof-of- principle for targeting cancer-secreted miRNAs as a novel approach to block the cancer-directed, pro-metastatic remodeling of the niche at early cancer stages for the prevention of metastasis. Our long-term objectives are to validate the miR-105 pathway in primary BC and establish standard approaches to identify patients suitable for therapies that target miR-105, to understand the global effects of cancer-secreted miRNAs, and to elucidate cancer-secreted, circulating miRNAs (e.g., miR-105) in BC patients as blood-borne markers for early diagnosis or prediction of metastasis. PUBLIC HEALTH RELEVANCE: Metastasis, the leading cause of mortality in cancer patients, is a multi-event process that involves interplay between cancer cells and the cancer-hosting niche. Our previous studies suggest that miR-105, a microRNA characteristically produced and secreted by metastatic breast cancer cells, can be transferred from cancer to the niche, and disrupt the anti-cancer "barriers" in the normal niche to promote metastasis. In the proposed study, we will dissect the dual role of miR-105 in regulating the potential of cancer cells to spread and in adapting the cancer niche, and will explore novel therapeutic strategies that target miR-105 to block this unique communication between cancer and host, and ultimately, to prevent metastasis.

描述（由申请人提供）：MicroRNA (miRNA) 似乎在癌症进展和转移过程中介导癌细胞与其宿主生态位之间的相互作用中发挥作用。我们的初步研究表明，miR-105 在循环中的水平与早期乳腺癌 (BC) 患者的转移进展相关，其特征是由转移性 BC (MBC) 细胞表达和分泌。 MiR-105 下调紧密连接蛋白 ZO-1，其表达减少与 BC 患者的转移相关。 MiR-105 有效诱导 MBC 细胞迁移和增殖，并且可以通过 MBC 分泌的外泌体转移到癌症微环境中的正常上皮和内皮细胞，从而改变 ZO-1 表达和这些微环境细胞的屏障功能。在 在我们实验室建立的小鼠模型中，MBC分泌的外泌体和miRNA可以被各种组织中的细胞内化，并可以促进转移的发展。本研究的目的是剖析 miR-105 在调节癌细胞转移潜力和破坏癌症生态位中上皮和内皮“屏障”方面的双重作用，并探索针对 miR-105 的新治疗策略介导的促转移功能。在目标 1 中，将研究 miR-105 对癌细胞粘附、迁移、侵袭、增殖和贴壁依赖性生长的影响，以及 ZO-1 在介导这些影响中的作用。将鉴定额外的 miR-105 调节基因，并确定它们在介导 miR-105 效应中的作用。在目标 2 中，将确定癌症分泌的、外泌体转移的 miR-105 对正常上皮和内皮微环境细胞的影响，重点关注它们限制癌细胞侵袭和转移的“屏障”功能。 miR-105 介导的屏障破坏效应的大小和动力学将通过将上皮和内皮微环境细胞与分泌 miR-105 的 MBC 细胞共培养来确定。在目标 3 中，将使用 BC 小鼠异种移植模型确定 miR-105 对生态位适应和 BC 转移的体内影响。将评估miR-105干预的抗转移效果。这些对癌症分泌的 miRNA 的深入功能研究有助于肿瘤宿主环境的共同进化，将为疾病进展过程中癌症与宿主之间的动态沟通提供新的见解。这项研究还将为靶向癌症分泌的 miRNA 作为一种新方法提供原理证明，以阻止癌症早期阶段的微环境的定向、促转移重塑，从而预防转移。我们的长期目标是验证原发性 BC 中的 miR-105 通路，并建立标准方法来识别适合针对 miR-105 的治疗的患者，了解癌症分泌的 miRNA 的整体影响，并阐明癌症分泌的、 BC 患者中的循环 miRNA（例如 miR-105）作为早期诊断或预测转移的血源性标志物。 公共卫生相关性：转移是癌症患者死亡的主要原因，是一个多事件过程，涉及癌细胞和癌症宿主生态位之间的相互作用。我们之前的研究表明，miR-105是一种由转移性乳腺癌细胞特有产生和分泌的微小RNA，可以从癌症转移到微环境，并破坏正常微环境中的抗癌“屏障”以促进转移。在拟议的研究中，我们将剖析 miR-105 在调节癌细胞扩散潜力和适应癌症生态位方面的双重作用，并将探索针对 miR-105 的新治疗策略，以阻断癌症与癌症之间的这种独特通讯。宿主，并最终防止转移。