Transcriptomic Analysis of Chronic Hepatitis B and C and Liver Cancer Reveals MicroRNA-Mediated Control of Cholesterol Synthesis Programs.
Transcriptomic Analysis of Chronic Hepatitis B and C and Liver Cancer Reveals MicroRNA-Mediated Control of Cholesterol Synthesis Programs.
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DOI：
10.1128/mbio.01500-15
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发表时间：
2015-12-08
期刊：
影响因子：
6.4
通讯作者：
Sethupathy P
中科院分区：
文献类型：
--
作者：
Selitsky SR;Dinh TA;Toth CL;Kurtz CL;Honda M;Struck BR;Kaneko S;Vickers KC;Lemon SM;Sethupathy P
慢性乙型肝炎（CHB）、慢性丙型肝炎（CHC）及相关肝细胞癌（HCC）以胆固醇失衡和血脂异常为特征；然而，这些表型的关键调控驱动因素尚不完全清楚。利用基因表达微阵列和小rna的高通量测序，我们对CHB或CHC和HCC患者的非恶性和匹配癌组织样本中的microRNA （miRNA）和基因表达进行了综合分析。我们还在基于细胞的系统中进行了特异性mirna的后续功能研究。这些研究得出了四个主要发现。首先，影响胆固醇稳态的途径在慢性病毒性肝炎，尤其是肿瘤组织中的基因失调中被过度表达。其次，对于每种疾病状态，鉴定出特异性miRNA签名，包括先前未与慢性病毒性肝炎相关的miRNA，例如CHC中的miR-1307。值得注意的是，包括miR-27和miR-224在内的一些miRNA是所有四种疾病状态（CHB、CHC、CHB相关HCC和CHC相关HCC）的miRNA特征的组成部分。第三，利用基因表达数据的统计模拟方法（miRHub），我们确定了慢性病毒性肝炎和HCC中控制胆固醇稳态途径的候选主miRNA调节因子，包括miR-21、miR-27和miR-33。最后，我们在人肝癌细胞中验证了miR-21和miR-27都能显著抑制胆固醇合成，并且miR-27部分通过调控限速酶3-羟基-3-甲基-戊二酰辅酶A （HMG-CoA）还原酶（HMGCR）的编码基因来实现。乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）是两种系统发育无关的嗜肝病毒，它们持续感染全世界数亿人，通常导致慢性肝病和肝细胞癌（HCC）。慢性乙型肝炎（CHB）、慢性丙型肝炎（CHC）及相关的肝细胞癌（HCC）常导致胆固醇失衡和血脂异常。然而，在这些疾病状态下脂质通路失调的调节机制尚不完全清楚。MicroRNAs （miRNAs）已成为脂质稳态的关键调节剂。在这里，我们使用基因组，分子和生化策略的混合来确定驱动慢性病毒性肝炎和HCC脂质表型的关键mirna。这些发现提供了miRNA在慢性病毒性肝炎中的全景视图，这可能有助于开发新的和更有效的基于miRNA的治疗策略。
Chronic hepatitis B (CHB), chronic hepatitis C (CHC), and associated hepatocellular carcinoma (HCC) are characterized by cholesterol imbalance and dyslipidemia; however, the key regulatory drivers of these phenotypes are incompletely understood. Using gene expression microarrays and high-throughput sequencing of small RNAs, we performed integrative analysis of microRNA (miRNA) and gene expression in nonmalignant and matched cancer tissue samples from human subjects with CHB or CHC and HCC. We also carried out follow-up functional studies of specific miRNAs in a cell-based system. These studies led to four major findings. First, pathways affecting cholesterol homeostasis were among the most significantly overrepresented among genes dysregulated in chronic viral hepatitis and especially in tumor tissue. Second, for each disease state, specific miRNA signatures that included miRNAs not previously associated with chronic viral hepatitis, such as miR-1307 in CHC, were identified. Notably, a few miRNAs, including miR-27 and miR-224, were components of the miRNA signatures of all four disease states: CHB, CHC, CHB-associated HCC, and CHC-associated HCC. Third, using a statistical simulation method (miRHub) applied to the gene expression data, we identified candidate master miRNA regulators of pathways controlling cholesterol homeostasis in chronic viral hepatitis and HCC, including miR-21, miR-27, and miR-33. Last, we validated in human hepatoma cells that both miR-21 and miR-27 significantly repress cholesterol synthesis and that miR-27 does so in part through regulation of the gene that codes for the rate-limiting enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase (HMGCR). Hepatitis B virus (HBV) and hepatitis C virus (HCV) are phylogenetically unrelated hepatotropic viruses that persistently infect hundreds of millions of people world-wide, often leading to chronic liver disease and hepatocellular carcinoma (HCC). Chronic hepatitis B (CHB), chronic hepatitis C (CHC), and associated HCC often lead to cholesterol imbalance and dyslipidemia. However, the regulatory mechanisms underlying the dysregulation of lipid pathways in these disease states are incompletely understood. MicroRNAs (miRNAs) have emerged as critical modulators of lipid homeostasis. Here we use a blend of genomic, molecular, and biochemical strategies to identify key miRNAs that drive the lipid phenotypes of chronic viral hepatitis and HCC. These findings provide a panoramic view of the miRNA landscape in chronic viral hepatitis, which could contribute to the development of novel and more-effective miRNA-based therapeutic strategies.