Circle RNA Regulation of Lung Cancer Metastasis

肺癌是美国癌症相关死亡的主要原因，每10年约有13.2万人死亡， 年虽然肺腺癌的靶向治疗提高了总生存率，但肺腺癌的靶向治疗也取得了类似进展。 鳞状细胞癌（LUSC）的发病率一直处于停滞状态。通过癌症基因组进行广泛的分子分析 Atlas（TCGA）的研究结果显示，LUSC肿瘤具有高度特异性，很少由单独的可操作性驱动。 途径。此外，转移，而不是原发性肿瘤，是大多数癌症相关死亡的原因。 然而，对LUSC如何传播的机制基础知之甚少。在本提案中，我们 将研究环状RNA（circRNA），CDR1as，在其调节LUSC转移中的作用。探讨 CDR1as对LUSC转移的调节作用，我们最近开发了复杂的LUSC模型 转移到人类常见疾病的部位通过将临床LUSC TCGA数据与我们的小鼠 在这些模型中，我们已经鉴定了CDR1as作为LUSC转移的关键驱动因素。我们已经发现，CDR1as发挥了 在稳定小脑变性相关蛋白1（CDR1）的编码mRNA转录中起关键作用。我们发现 CDR1a和CDR1对于LUSC转移都是必需的，并且CDR1单独过表达就足够了 促进LUSC转移。我们发现CDR1与几种特异的高尔基体运输蛋白相互作用， 表达与LUSC存活率低相对应，并与上皮-间充质转化紧密相关。 (EMT)程序.此外，我们还发现了促进其RNA稳定性的CDR1as的关键结构元件 和表达水平。综上所述，关键问题出现了，如：1）CDR1如何在高尔基体中运输 囊泡促进迁移和转移？2)寡核苷酸介导的靶向CDR1as能否阻断LUSC转移 并延长生存期本提案的目的是确定CDR1如何促进LUSC转移 通过高尔基体的运输我们还将确定中断结构的生物学和治疗意义， CDR1as的组成部分。

Lung cancer is the leading cause of cancer-related deaths in the U.S., accounting for about 132,000 deaths per year. While targeted therapies of lung adenocarcinoma have improved overall survival, similar advances in lung squamous carcinoma (LUSC) have been stagnant. Extensive molecular profiling through the Cancer Genome Atlas (TCGA) effort revealed that LUSC tumors are highly idiosyncratic and rarely driven by solitary actionable pathways. Also, metastasis, rather than primary tumors, is responsible for the majority of cancer-related deaths. However, the mechanistic underpinnings of how LUSC spreads are very poorly understood. In this proposal, we will investigate the roles of a circle RNA (circRNA), CDR1as, on its regulation of LUSC metastasis. To investigate the regulatory role of CDR1as on LUSC metastasis, we have recently developed sophisticated LUSC models that metastasize to sites common to human disease. By integrating clinical LUSC TCGA data with our mouse models, we have identified CDR1as as a key driver of LUSC metastasis. We have found that CDR1as plays a key role in stabilizing the coding mRNA transcript for cerebellar degeneration-related protein 1 (CDR1). We found that CDR1as and CDR1 are each necessary for LUSC metastasis, and CDR1 over-expression alone is sufficient to promote LUSC metastasis. We found CDR1 interacts with several specific Golgi trafficking proteins, and CDR1 expression corresponds with poor LUSC survival and tightly couples with an epithelial-mesenchymal transition (EMT) program. Additionally, we have found key structural elements of CDR1as that promote its RNA stability and expression levels. Taken together, key questions arise, such as: 1) How does CDR1 trafficking in the Golgi vesicles promote migration and metastasis? 2) Can oligo-mediated targeting of CDR1as block LUSC metastasis and prolong survival? The objectives of this proposal are to define how CDR1 promotes LUSC metastasis through Golgi trafficking. We will also determine the biologic and therapeutic implications of interrupting structural elements of CDR1as.