Abstract
Circulating microRNAs (miRNAs) can be employed as biomarkers to diagnose liver and other diseases. Noninvasive approaches are needed to complement and improve the current strategies for screening for biomarkers liver cirrhosis. We determined whether the serum levels of miRNAs can distinguish between chronic hepatitis B (CHB) and CHB-induced cirrhosis (HBC) and investigated the potential mechanisms involved. We found that serum miR-27a was significantly up-regulated in HBC, distinguishing HBC from CHB and healthy controls (Ctrl) (P<0.0001, the area of under the curve (AUC) =0.82 and 0.87, respectively). Specifically, when miR-27a was combined with miR-122, HBC was differentiated from CHB with an AUC=0.94. The serum miR-27a level in HBC patients with hepatic decompensation was significantly higher than that in patients with compensated HBC (P=0.0009). MiR-27a was also significantly up-regulated in the serum of rats with DMN-induced liver cirrhosis compared to that in saline-treated rats (P<0.0001). Furthermore, the down-regulation of miR-27a inhibited the proliferation and overexpression of miR-27a in activated hepatic stellate cells (HSCs) through the up-regulation of α-SMA and COL1A2 expression by targeting PPARγ, FOXO1, APC, P53 and RXRα. Our study demonstrated that circulating miR-27a can be used as a predictor for the activation of HSCs and the occurrence and development of HBC.
Highlights
Liver cirrhosis, one of the most common nonneoplastic causes of mortality worldwide, is characterized by the replacement of liver tissue by fibrosis and regenerative nodules [1]
We found that serum miR-27a was significantly up-regulated in HBC, distinguishing HBC from chronic hepatitis B (CHB) and healthy controls (Ctrl) (P
5 candidate miRNAs were chosen because they were among in the 38 deregulated miRNAs in HBC compared with CHB
Summary
One of the most common nonneoplastic causes of mortality worldwide, is characterized by the replacement of liver tissue by fibrosis (scar tissue) and regenerative nodules (lumps that result from the attempted repair of damaged tissue) [1]. The principal causes of this disease include chronic viral infection, excess alcohol consumption, metabolic syndrome, and autoimmune disorders. Chronic hepatitis B (CHB) is a major cause of liver cirrhosis (HBC) in China [2, 3]. Up to 40% of patients with CHB progress to chronic end-stage liver disease or hepatocellular carcinoma (HCC) during their lifetime [4]. Liver biopsy has traditionally been considered the gold standard for diagnosing cirrhosis [5]. This invasive technique has some limitations, including morbidity and mortality, observer variability, and sampling variation [6, 7]. Finding an effective method and reliable biomarkers to ensure an early diagnosis www.impactjournals.com/oncotarget would play a pivotal role in improving the treatment and prognosis of HBC
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