Role of microRNAs in malignant progression

描述（由申请人提供）：越来越明显的是，癌症的发病机制可能涉及一个名为microRNAs的小非编码rna超家族。虽然许多microrna的致癌或肿瘤抑制功能已经被表征，但microrna在介导转移中的作用直到最近才被我们实验室和其他几个小组的工作所解决。我目前是一名生命科学研究基金会博士后，近期目标是在怀特黑德生物医学研究所的鲍勃·温伯格博士的指导下完成额外的1-2年的研究。在我最初的筛选中，我确定了三种在人类乳腺癌细胞系中最显著上调的microrna: miR-155， miR-9和mir - 10b。随后，我发现mir - 10b是一种twist调控的microRNA，在转移性癌细胞和患者的转移性乳腺肿瘤中高度表达。这个microRNA抑制HOXD10蛋白的合成，允许促转移基因产物RhoC的表达。重要的是，mir - 10b在非转移性乳腺癌细胞中的过表达使其能够在体内侵袭和转移。这些发现代表了microRNA过表达可以促进转移发展的第一个功能证据。由于靶向miR-l0b是否会抑制恶性进展尚不清楚，我现在建议结合遗传学和药理学方法来研究miR-l0b功能丧失在发展和乳腺癌转移中的作用。此外，根据先前描述的观察结果，在组织学上可检测到肺微转移的证据之前，miR-l0b在原发性乳腺肿瘤中的过表达会导致肺巨噬细胞积聚，我将探讨miR-l0b在转移进展中的细胞非自主性作用。同时，我将描述在我最初的筛选中突出的第二个候选microRNA miR-9在上皮-间质转化、血管生成和转移中的作用，因为miR-9是唯一预测靶向e -钙粘蛋白的microRNA， e -钙粘蛋白是一种主要的粘附分子，其缺失与肿瘤侵袭和转移密切相关。长期目标是了解microrna在调节转移中的作用，并为恶性疾病开发新的候选疗法。

DESCRIPTION (provided by applicant): It has become increasingly evident that cancer pathogenesis can involve a superfamily of small non-coding RNAs named microRNAs. While the oncogenic or tumor-suppressing functions of a number of microRNAs have been characterized, the role played by microRNAs in mediating metastasis was addressed only recently by work from our laboratory and several other groups. I am currently a Life Sciences Research Foundation Postdoctoral Fellow with the immediate goal of completing additional 1-2 years of mentored research with Dr. Bob Weinberg at the Whitehead Institute for Biomedical Research. In my initial screening, I identified three microRNAs that are most significantly upregulated in human breast cancer cell lines: miR-155, miR-9, and miR-l0b. Subsequently, I identified miR-l0b as a Twist-regulated microRNA that is highly expressed in metastatic cancer cells as well as in metastatic breast tumors from patients. This microRNA inhibits synthesis of the HOXD10 protein, permitting the expression of the pro-metastatic gene product, RhoC. Importantly, overexpression of miR-l0b in otherwise-non- metastatic breast cancer cells enables them to invade and metastasize in vivo. These findings represent the first functional evidence that overexpression of a microRNA can contribute to the development of metastasis. Since it remains unexplored whether targeting miR-l0b will inhibitmalignant progression, I now propose to combine genetic and pharmacological approaches to study miR-l0b loss-of-function effects in development and in breast cancer metastasis. Moreover, based on a previously undescribed observation that miR-l0b overexpression in the primary mammary tumor leads to lung macrophage accumulation prior to evidence of histologically detectable pulmonary micrometastases, I will explore the cell non-autonomous effects of miR-l0b in metastatic progression. In parallel, I will characterize the role of a second candidate microRNA that stood out in my initial screen, miR-9, in epithelial-mesenchymal transitions, angiogenesis, and metastasis, given that miR-9 is the only microRNA that is predicted to target E-cadherin, a major adhesion molecule whose loss is strongly implicatedin tumor invasion and metastasis. The long-term goal is to understand the role of microRNAs in regulating metastasis, and to develop new candidatetherapies for malignant diseases. RELEVANCE: Not only does this study illuminate the genetic and molecular basis of tumor metastasis, but it also has implications for breast cancer treatment. This will be the first proof-of-concept study of whether inhibiting a specific microRNA can prevent metastasis. Investigation of the cell non-autonomous effects of metastasis- mediating microRNAs may lead to discovery of endocrine proteins that have therapeutic potentials.