Systematic Characterization of Small Nucleolar RNAs in Cancer

摘要 尽管最近癌症的治疗方法取得了进展，但大多数癌症类型仍然缺乏充分的 特色和有效的靶向治疗。这种不足导致了对替代产品的需求， 以前未考虑过的改善疾病诊断、预后和患者的治疗方法 生存结果。最近，我们对大样本中的小核仁RNA(SnoRNAs)进行了综合分析。 患者样本的数量，并确定了46个具有广谱临床意义的snoRNA，其中12个 或更多类型的癌症。我们开发了一个数据门户，癌症中的snoRNA(SNORic)，它允许研究人员 探讨个体snoRNAs在肿瘤中的意义。自那以后，SNORIC已经被访问了10万次 它于2017年发布，表明它在生物医学研究界产生了广泛的影响。我们提供了首字母 遗传学证据表明snoRNAs的高表达促进了乳腺肿瘤的发生 腺体恶性肿瘤。我们从机制上证明了SNORD46在促进 TNBC的发生、生长、侵袭和发展。因此，阐明snoRNAs在 促进肿瘤发生是开发一类基于snoRNA的新型分子的第一步 生物标志物和治疗靶点。 我们的中心假设是，snoRNAs是促进癌症发生的重要RNA靶点， 进展和耐药性，可通过基于反义寡核苷酸的体内减弱 靶向治疗。在特定的目标1中，我们将描述这些snoRNAs在 三阴性乳腺癌(目标1.1)。我们将演示这些snoRNA的分子机制 促进TNBC细胞的增殖、迁移和侵袭(目标1.2)。我们将证明这种反义 基于寡核苷酸的snoRNA靶向治疗有效地抑制了体内TNBC的生长(Aim 1.3)。我们会 通过分子QTL分析评估和解释因果效应(目标1.4)。在具体目标2中，我们将确定 三个snoRNAs在乳腺癌耐药中的作用(目标2.1)。我们将会理解分子 通过多组学数据研究耐药机制(目标2.2)。扩大我们对毒品的看法 ，我们将根据单个snoRNA的表达来预测药物反应，同时 深度学习(目标2.3)。我们将研究基于snoRNA的亚型之间的药物反应效应(目标2.4)。 我们将建立一个方便用户的数据门户，以发布通过综合分析产生的数据(AIM 2.5)。 这项研究将显著提高snoRNAs的预后、诊断和治疗潜力； 缺乏这项研究工作将极大地阻碍基于snoRNA的治疗考虑的实现 为癌症患者准备的。

Abstract Despite recent advancements in treatment options for cancer, a majority of cancer types continue to lack fully characterized and effective targeted therapies. This insufficiency has resulted in the demand for alternative, previously unconsidered treatment approaches to improve disease diagnostics, prognoses, and patient survival outcomes. Recently, we performed integrative analysis for small nucleolar RNA (snoRNAs) in a large number of patient samples and identified 46 snoRNAs that exhibit broad-spectrum clinical significance with 12 or more types of cancer. We developed a data portal, snoRNA in cancers (SNORic), which allows researchers to explore the significance of individual snoRNAs in cancer. SNORic has been accessed >100,000 times since its release in 2017, suggesting its broad impact in the biomedical research community. We provided initial genetic evidence indicating that elevated expression of snoRNAs facilitated the tumorigenesis of mammary gland malignancies. Mechanistically we demonstrated that SNORD46 plays important roles in promoting the initiation, growth, invasion and progression of TNBC. Therefore, elucidation of the roles of snoRNAs in promoting tumorigenesis serves as the first step in the development of a novel class of snoRNA-based biomarkers and therapeutic targets. Our central hypothesis is that snoRNAs serve as essential RNA targets in promoting cancer initiation, progression, and drug resistance, which could be attenuated in vivo by an antisense oligonucleotide-based targeted therapy. In specific aim 1, we will delineate the diagnostic and prognostic values of these snoRNAs in triple-negative breast cancer (Aim 1.1). We will demonstrate the molecular mechanism that these snoRNAs promote TNBC cell proliferation, mobility and invasion (Aim 1.2). We will demonstrate that antisense oligonucleotide-based snoRNA targeted therapy effectively inhibits TNBC growth in vivo (Aim 1.3). We will evaluate and interpret causal effects through molQTL analysis (Aim 1.4). In specific aim 2, we will determine the role of three snoRNAs in breast cancer drug resistance (Aim 2.1). We will understand the molecular mechanisms for drug resistance through multi-omics data (Aim 2.2). To expand our perspective on drug resistance, we will predict the drug response from individual snoRNA expression with the augmentation of deep learning (Aim 2.3). We will study the drug responses effects among snoRNA-based subtypes (Aim 2.4). We will build a user-friendly data portal for releasing the date generated through integrative analysis (Aim 2.5). This study will significantly advance the prognostic, diagnostic, and therapeutic potential of snoRNAs; the absence of this research work will greatly hinder the realization of snoRNA-based therapeutic considerations for cancer patients.