A novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition

一种新的lncRNA反应和异种受体介导的药物代谢调节和 处置 摘要 药物代谢和处置是重要的异种生物反应。长非编码RNA(LncRNAs) 是长度大于200个核苷酸(NT)的非编码RNA，并且不具有蛋白质编码潜力。 尽管lncRNAs的许多生物学功能已被认识，但是否以及如何认识尚不清楚。 LncRNA可以调节药物代谢酶和转运体的表达，如果是这样的话，是否 法规与癌症的化疗耐药有关。通过对癌症非编码的综合分析 我们的初步研究发现，505个癌细胞株的基因组和高通量药物筛选数据 并从功能上表征了一组ADME(药物的吸收、分布、代谢和排泄) 化疗耐药的lncRNA，包括LINC00992，其上调与对更多 超过100种化学化合物，可能通过调节药物代谢酶和转运蛋白 与异种核受体相互作用。我们假设ADME化疗耐药的失调 LncRNAs是肿瘤化疗耐药发生的重要因素。从机械上讲，ADME 化疗耐药的lncRNA通过调节药物代谢酶和 负责化疗药物新陈代谢和处置的转运体。我们提出三个建议 具体目的是为了验证我们的假设：在目标1中，我们将进行生物信息学分析和分子克隆 IncRNAs与肿瘤化疗耐药和临床预后相关。目标2：我们将发挥作用 包括LINC00992在内的ADME耐药基因在体内和体外肿瘤中的应用研究 化疗模型。在目标3：我们将确定ADME化疗耐药的机制 包括LINC00992在内的lncRNAs调控药物代谢酶和转运蛋白的表达。 化疗仍然是癌症患者临床治疗的主要手段，但化疗耐药是一种 需要克服的重大挑战。了解新的lncRNA反应和异源核受体- 介导的化疗耐药将有助于提供新的策略，以提高治疗效果，避免 化疗耐药性的发展。

A novel lncRNA-responsive and xenobiotic receptor-mediated regulation of drug metabolism and disposition Abstract Drug metabolism and disposition are essential xenobiotic responses. The long non-coding RNAs (lncRNAs) are non-coding RNAs larger than 200 nucleotides (nt) in length and do not have protein-coding potentials. Although many of the biological functions of lncRNAs have been recognized, it is unclear whether and how lncRNAs can regulate the expression of drug-metabolizing enzymes and transporters and if so, whether the regulations are implicated in cancer chemo-resistance. Through integrative analysis of cancer non-coding genomic and high-through drug screening data of 505 cancer cell lines, our preliminary study have discovered and functionally characterized a group of ADME(drug absorption, distribution, metabolism, and excretion) chemo-resistance lncRNAs, including LINC00992, whose up-regulation is associated with resistance to more than 100 chemotherapy compounds and may regulate drug-metabolizing enzymes and transporters through interacting with xenobiotic nuclear receptor. We hypothesize that dysregulation of ADME chemo-resistance lncRNAs is an important contributor for the development of cancer chemo-resistance. Mechanistically, ADME chemo-resistance lncRNAs affect chemo-resistance through their regulation of drug-metabolizing enzymes and transporters that are responsible for the metabolism and disposition of chemotherapy drugs. We propose three specific aims to test our hypotheses: In Aim 1, we will perform bioinformatic analysis and molecularly clone of lncRNAs associated with cancer chemo-resistance and clinical prognosis. In Aim 2: we will functional characterize of ADME chemo-resistance lncRNAs, including LINC00992, using in vivo and in vitro cancer chemotherapy models. In Aim 3: we will determine the mechanism by which ADME chemo-resistance lncRNAs, including LINC00992, regulate the expression of drug-metabolizing enzymes and transporters. Chemotherapy remains a mainstay in the clinical management of cancer patients, but chemo-resistance is a major challenge to overcome. Understanding the novel lncRNA responsive and xenobiotic nuclear receptor- mediated chemo-resistance will help provide novel strategies to enhance therapeutic efficacy and avoid the development of chemo-resistance.