miR-200c促进肿瘤寡灶型转移向多灶型转移演进的机制研究

Oligometastasis(es), in contrast to the widely spread polymetastasis, is characterized by a limited number of metastasis(es). About 25% of oligometastatic patients, treated with metastasis-directed therapies, could achieve long-term survival. However cancer in the rest majority of oligometastatic patients will progress to polymetastases. Therefore, understanding oligometastasis(es) tumor biology will improve patient selection for curative treatments. We recently showed that a microRNA signature could identify oligometastatic patients fail to undergo polymetastatic progression. In addition, we demonstrated oligometastasis(es) as a distinct biologic entity regulated, in part, by miR-200c which promotes oligo- to polymetastatic progression. We have also developed reproducible clinically relevant MDA-MB-435-based pre-clinical animal models for oligometastatic and polymetastatic progression. We hypothesize that miR-200c promotes oligometastatic to polymetastatic progression by enhancing polymetastatic colonization. We have found a productive and multi-disciplinary collaboration between the investigators from cancer biology, bioinformatics, clinical pathology and clinical oligometastasis research. The present application, aiming to elucidate mechanisms of polymetastatic progression by characterizing critical miR-200c gene targets, will identify targetable rate-limiting events of polymetastatic colonization. Two specific aims will be conducted to address the central hypothesis. In Aim 1, we will determine whether Sec23a, a confirmed miR-200c gene target, regulates tumor cell-associated secretome function to mediate polymetastatic progression. The expression of Sec23a will be stably knocked down in order to assess changes in metastatic progression. We will also determine its association with oligo-/polymetastatic progression as well as survival. Since miR-200c has 681 putative targets, alternative miR-200c gene targets may also be important in mediating the full activity of miR-200c during polymetastatic progression. In Aim 2, we proposed a genomic-based approach to identify and characterize novel miR-200c gene targets in the context of miR-200c stable overexpression. These experiments, highly complementary and synergistic to those in Aim1, will provide a more unbiased and comprehensive mechanistic understanding on miR-200c in polymetastatic progression. Findings from these studies will lead to development of targets and novel treatment approaches for preventing polymetastatic progression

我们的前期临床和基础研究展示了转移灶数目有限、进展缓慢的寡灶型转移是一个有异于进展迅速的多灶型转移的分子生物学、临床诊断和治疗的新实体。25%的寡灶型病人在接受寡灶型转移针对性治疗后能达治愈，从寡灶向多灶型转移的演变是治疗失败的根本原因。我们首次显示了miR-200c的表达能够分辩临床寡灶向多灶型转移病人。在此，我们富有创意地提出应用一个多学科（肿瘤生物学、生物信息学、基础医学和临床医学)交叉的研究手段, 从分子、细胞和肿瘤整体的不同层面，来阐明miR-200c对促进寡灶向多灶转移演进的基因调控机制，以及对寡灶型转移针对性治疗的临床应用意义和影响。此外，我们创建的、与临床寡／多灶型转移相关的动物模型为此项目的顺利实施提供了关键的技术保障。通过这一研究，我们期待能为临床预测和阻止由寡灶型向多灶型型转移的演变寻找到重要的靶点和突破口。此项研究不仅富有科学创意，还有着近期和长远的社会经济意义。

项目背景：我们的前期临床和基础研究展示了转移灶数目有限、进展缓慢的寡灶型转移是一个有异于进展迅速的多灶型转移的分子生物学、临床诊断和治疗的新实体。25%的寡灶型病人在接受寡灶型转移针对性治疗后能达治愈，从寡灶向多灶型转移的演变是治疗失败的根本原因。我们首次显示了miR-200c的表达能够分辩临床寡灶向多灶型转移病人。本课题我们富有创意地提出应用一个多学科（肿瘤生物学、生物信息学、基础医学)交叉的研究手段,从分子、细胞和肿瘤整体的不同层面，来阐明miR-200c对促进寡灶向多灶转移演进的基因调控机制。研究内容：本项目的研究主要目标就是探讨miR-200c 是否能够通过作用于它的标靶基因Sec23a 而促进多灶型转移，进而更深入地揭示miR-200c 促进多灶型转移的生物功能和分子生物学机制。主要研究内容：(1) 研究和描述miR-200c 过表达对体内和体外转移特性的影响；（2）分析稳定沉默Sec23a 对体外生物学特征的影响；（3）分析稳定沉默Sec23a 的表达对分泌蛋白组 (secretome) 的影响；（4）分析稳定沉默Sec23a 的表达对体内少/多灶型转移进程的影响。重要结果：（1）寡灶型细胞株稳定上调miRNA200c后体外克隆形成能力、迁移能力和侵袭能力均有所提高，且呈现出多灶型细胞株的特性;(2) 乳腺癌寡灶型细胞株稳定敲低Sec23a基因后, 细胞的增殖特性并没有明显变化, 但细胞的迁移、侵袭能力和克隆形成能力均增强;(3) 稳定沉默Sec23a 的表达对分泌蛋白组 (secretome) 有显著的影响，为未来研究找到介导Sec23a抑制多灶性转移的靶基因提供了实验依据。科学意义：通过这一研究，我们期待在后继研究中能为临床预测和阻止由寡灶型向多灶型型转移的演变寻找到重要的靶点和突破口。此项研究有临床转化的意义。

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