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）：在癌症进展和转移过程中，MicroRNAs （miRNAs）似乎在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）患者的转移进展有关，它是转移性BC （MBC）细胞的特征性表达和分泌。MiR-105下调紧密连接蛋白ZO-1，其表达降低与BC患者的转移有关。MiR-105能有效诱导MBC细胞的迁移和增殖，并可通过MBC分泌的外泌体转移到肿瘤生态位中的正常上皮和内皮细胞，从而改变这些生态位细胞的ZO-1表达和屏障功能。在