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miR-200c Mediates Suppression of Anoikis Resistance by Targeting an Autocrine Sig

miR-200c 通过靶向自分泌信号介导失巢凋亡抵抗的抑制

基本信息

批准号：
8256463
负责人：
Erin Nicole Howe
金额：
$ 1.04万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-16 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8256463
关键词：
3&apos Untranslated Regions Adhesions Affect Anoikis Apoptosis Autocrine Communication Binding Sites Blood Circulation Breast Cancer Cell Cancer Patient Cancer cell line Cell Count Cell Surface Receptors Cells Data Development Embolism Extracellular Matrix Face Goals Hormone Receptor In Vitro Influentials Ligands Lung Lymphatic Malignant Epithelial Cell Malignant Neoplasms Mediating MicroRNAs Micrometastasis Microtubules Molecular NTF3 gene Neoplasm Metastasis Neurotrophin 3 Outcome Patients Phenotype Physiological Play Proteins Receptor Protein-Tyrosine Kinases Relapse Repression Resistance Role Sampling Seeds Signal Pathway Signal Transduction Site Testing Therapeutic Time Travel Up-Regulation Woman autocrine cancer cell cancer stem cell cancer type chemotherapy in vivo in vivo Model killings malignant breast neoplasm migration novel therapeutics prevent programs receptor restoration triple-negative invasive breast carcinoma

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify a new treatment for patients with triple negative breast cancer who have not responded to, or relapsed while on, traditional chemotherapeutics. Patients with this particular subtype of breast cancer have extremely limited therapeutic options due to the absence of hormone receptors. Thus, determining the molecular mechanisms that drive this cancer and identifying new therapeutic strategies is a high priority. Preliminary data from my lab and others demonstrates that miR-200c suppresses migration, invasion, resistance to microtubule targeting agents and a cancer stem cell phenotype. I have demonstrated that restoring miR-200c to triple negative breast cancer cell lines also suppresses their resistance to anoikis. Anoikis is a form of apoptosis that is initiated when the cells lose their interactions with the extracellular matrix, and it has been suggested as a physiological barrier to metastasis. Resistance to anoikis may allow survival of the carcinoma cells during systemic circulation, when they form emboli in the vasculature or lymphatics but are deprived of matrix adhesion. I have found that miR-200c directly targets a cell surface receptor implicated in anoikis resistance in multiple cancer types, neurotrophic tyrosine receptor kinase B (TrkB). Furthermore, neurotrophin 3 (NTF3), a ligand for TrkB has 2 predicted miR-200c binding sites in the 3' UTR. Taken together, this data leads to my hypothesis that miR-200c enhances anoikis sensitivity in breast cancer cells through targeting of a TrkB/NTF3 signaling pathway. The following specific aims test this hypothesis. Specific aim 1: Determine if an autocrine signaling loop in TrkB/NTF3 contributes to the ability of miR- 200c to suppress anoikis resistance in breast cancer cells. Specific aim 2: Determine if loss of miR-200c correlates with expression of TrkB and NTF3 in breast cancer patient samples. Specific aim 3: Study the ability of miR- 200c to sensitize aggressive breast cancer cells to anoikis in an in vivo model of metastasis. By furthering our understanding of how miR-200c affects anoikis resistance in breast cancer, we move closer to the development of this influential miRNA as a therapeutic option. PUBLIC HEALTH RELEVANCE: Breast cancer is the second most deadly cancer a woman will face in her lifetime, with no real treatment options for patients with triple negative breast cancer who do not respond to, or relapse while on, traditional chemotherapy. We have identified a miRNA, miR-200c, that is able to sensitize cells to an inherent cellular program that drives them to die when they are unattached. By utilizing miR-200c as a non-traditional chemotherapeutic, we hope to prevent metastasis by killing cancer cells before they are able to colonize metastatic sites.

描述（由申请人提供）：该项目的长期目标是为三阴性乳腺癌患者确定一种新的治疗方法，这些患者对传统化疗药物无反应或复发。由于缺乏激素受体，这种特殊亚型的乳腺癌患者的治疗选择非常有限。因此，确定驱动这种癌症的分子机制并确定新的治疗策略是一个高度优先事项。来自我实验室和其他实验室的初步数据表明，miR-200 c抑制迁移、侵袭、对微管靶向剂的抗性和癌症干细胞表型。我已经证明，将miR-200 c恢复到三阴性乳腺癌细胞系也抑制了它们对失巢凋亡的抵抗。失巢凋亡是细胞失去与细胞外基质的相互作用时引发的一种细胞凋亡形式，它被认为是转移的生理屏障。抗失巢凋亡可能允许癌细胞在体循环期间存活，当它们在脉管系统或血管系统中形成栓塞但被剥夺基质粘附时。我发现miR-200 c直接靶向与多种癌症类型中的失巢凋亡抗性有关的细胞表面受体，神经营养酪氨酸受体激酶B（Trk B）。此外，神经营养蛋白3（NTF 3），TrkB的配体，在3' UTR中具有2个预测的miR-200 c结合位点。综上所述，这些数据导致了我的假设，即miR-200 c通过靶向TrkB/NTF 3信号通路增强乳腺癌细胞的失巢凋亡敏感性。以下具体目标检验了这一假设。具体目标1：确定TrkB/NTF 3中的自分泌信号环是否有助于miR-200 c抑制乳腺癌细胞中失巢凋亡抵抗的能力。具体目标2：确定乳腺癌患者样本中miR-200 c的缺失是否与TrkB和NTF 3的表达相关。具体目标3：研究miR-200 c在体内使侵袭性乳腺癌细胞对失巢凋亡敏感的能力转移模型。通过进一步了解miR-200 c如何影响乳腺癌的失巢凋亡抵抗，我们更接近于开发这种有影响力的miRNA作为治疗选择。公共卫生相关性：乳腺癌是女性一生中面临的第二大致命癌症，对于三阴性乳腺癌患者没有真实的治疗选择，这些患者对传统化疗没有反应或复发。我们已经确定了一种miRNA，miR-200 c，它能够使细胞对一种内在的细胞程序敏感，这种程序在它们未附着时驱动它们死亡。通过利用miR-200 c作为一种非传统的化疗药物，我们希望通过在癌细胞能够定殖转移部位之前杀死癌细胞来预防转移。