Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
PLoS One. 2011;6(8):e23937. doi: 10.1371/journal.pone.0023937. Epub 2011 Aug 23.
MicroRNAs miR-122, miR-34a, miR-16 and miR-21 are commonly deregulated in liver fibrosis and hepatocellular carcinoma. This study examined whether circulating levels of these miRNAs correlate with hepatic histological disease severity in patients with chronic hepatitis C infection (CHC) or non-alcoholic fatty-liver disease (NAFLD) and can potentially serve as circulating markers for disease stage assessment. We first used an in vitro model of hepatitis C virus (HCV) infection to measure the extracellular levels of these four miRNAs. Whereas miR-21 extracellular levels were unchanged, extracellular levels of miR-122, miR-34a and to a lesser extent miR-16, steadily increased during the course of HCV infection, independently of viral replication and production. Similarly, in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher than in control individuals, while miR-21 levels were unchanged. There was no correlation between the serum levels of any of these microRNAs and HCV viral loads. In contrast, miR-122 and miR-34a levels positively correlated with disease severity. Identical results were obtained in an independent cohort of CHC patients. We extended the study to patients with NAFLD. As observed in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher in NAFLD patients than in controls, while miR-21 levels were unchanged. Again, miR-122 and miR-34a levels positively correlated with disease severity from simple steatosis to steatohepatitis. In both CHC and NAFLD patient groups, serum levels of miR-122 and miR-34a correlated with liver enzymes levels, fibrosis stage and inflammation activity. miR-122 levels also correlated with serum lipids in NAFLD patients.
Serum levels of miR-34a and miR-122 may represent novel, noninvasive biomarkers of diagnosis and histological disease severity in patients with CHC or NAFLD.
microRNAs miR-122、miR-34a、miR-16 和 miR-21 在肝纤维化和肝细胞癌中通常失调。本研究检查了慢性丙型肝炎感染 (CHC) 或非酒精性脂肪性肝病 (NAFLD) 患者循环中这些 miRNA 的水平是否与肝组织学疾病严重程度相关，并且是否可能作为疾病阶段评估的循环标志物。我们首先使用丙型肝炎病毒 (HCV) 感染的体外模型来测量这四种 miRNA 的细胞外水平。虽然 miR-21 的细胞外水平没有变化，但 miR-122、miR-34a 的细胞外水平在 HCV 感染过程中稳步增加，而与病毒复制和产生无关。同样，在 CHC 患者中，miR-122、miR-34a 和 miR-16 的血清水平明显高于对照组，而 miR-21 水平不变。这些 microRNAs 中的任何一种的血清水平与 HCV 病毒载量均无相关性。相反，miR-122 和 miR-34a 水平与疾病严重程度呈正相关。在 CHC 患者的另一独立队列中获得了相同的结果。我们将研究扩展到 NAFLD 患者。与 CHC 患者一样，NAFLD 患者的血清 miR-122、miR-34a 和 miR-16 水平明显高于对照组，而 miR-21 水平不变。同样，miR-122 和 miR-34a 水平与单纯脂肪变性到脂肪性肝炎的疾病严重程度呈正相关。在 CHC 和 NAFLD 患者组中，miR-122 和 miR-34a 的血清水平与肝酶水平、纤维化阶段和炎症活动相关。miR-122 水平也与 NAFLD 患者的血清脂质相关。
血清 miR-34a 和 miR-122 水平可能是 CHC 或 NAFLD 患者诊断和组织学疾病严重程度的新型非侵入性生物标志物。
