Circulating MicroRNAs, miR‐21, miR‐122, and miR‐223, in patients with hepatocellular carcinoma or chronic hepatitis

Numerous studies have shown that aberrant microRNA (miRNA) expression is associated with the development and progression of various types of human cancer and serum miRNAs are potential biomarkers. This study examined whether some commonly deregulated miRNAs in hepatocellular carcinoma (HCC) are presented in serum of patients with HCC and can serve as diagnostic markers. Serum miRNAs (miR‐21, miR‐122, and miR‐223) were quantified by real‐time quantitative RT‐PCR in 101 patients with HCC and 89 healthy controls. In addition, 48 patients with chronic type B hepatitis were also analyzed for comparison. We found that the median levels of miR‐21, miR‐122, and miR‐223 were significantly higher in patients with HCC than those in healthy controls (P = 7.48 × 10−13, P = 6.93 × 10−9, and P = 3.90 × 10−12, respectively). However, these elevated serum miRNAs were also detected in patients with chronic hepatitis (P = 2.05 × 10−12, P = 4.52 × 10−16, and P = 1.65 × 10−11, respectively). Moreover, serum miR‐21 and miR‐122 in patients with chronic hepatitis were higher than in patients with HCC (P = 3.99 × 10−4 and P = 4.97 × 10−8), although no such significant difference was found for miR‐223. Receiver‐operator characteristic (ROC) curve analyses suggest that these serum miRNAs may be useful markers for discriminating patients with HCC or chronic hepatitis from healthy controls, but not patients with HCC from patients with chronic hepatitis. Our results indicate that serum miR‐21, miR‐122 and miR‐223 are elevated in patients with HCC or chronic hepatitis and these miRNAs have strong potential to serve as novel biomarkers for liver injury but not specifically for HCC. © 2010 Wiley‐Liss, Inc.

[1]  Zhaohui Huang,et al.  Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer , 2010, International journal of cancer.

[2]  Xi Chen,et al.  Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  Michael J Kerin,et al.  Circulating microRNAs as Novel Minimally Invasive Biomarkers for Breast Cancer , 2010, Annals of surgery.

[4]  S. Lowe,et al.  miR-221 overexpression contributes to liver tumorigenesis , 2009, Proceedings of the National Academy of Sciences.

[5]  C. Croce,et al.  MicroRNA 29b functions in acute myeloid leukemia. , 2009, Blood.

[6]  Frank D Sistare,et al.  Plasma MicroRNAs as sensitive and specific biomarkers of tissue injury. , 2009, Clinical chemistry.

[7]  G. Hirokawa,et al.  Plasma miR-208 as a biomarker of myocardial injury. , 2009, Clinical chemistry.

[8]  Cheng-Fu Xu,et al.  Association of MicroRNA-223 Expression with Hepatic Ischemia/Reperfusion Injury in Mice , 2009, Digestive Diseases and Sciences.

[9]  S. Thorgeirsson,et al.  Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties , 2009, Oncogene.

[10]  K. Ghoshal,et al.  MicroRNA-122 Inhibits Tumorigenic Properties of Hepatocellular Carcinoma Cells and Sensitizes These Cells to Sorafenib* , 2009, The Journal of Biological Chemistry.

[11]  G. Dore,et al.  Hepatitis B‐related hepatocellular carcinoma: epidemiological characteristics and disease burden , 2009, Journal of viral hepatitis.

[12]  George A. Calin,et al.  MicroRNA identification in plasma and serum: a new tool to diagnose and monitor diseases , 2009, Expert opinion on biological therapy.

[13]  Hsien-Da Huang,et al.  MicroRNA‐122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma , 2009, Hepatology.

[14]  L. Hood,et al.  Circulating microRNAs, potential biomarkers for drug-induced liver injury , 2009, Proceedings of the National Academy of Sciences.

[15]  C. Croce,et al.  microRNA-205 regulates HER3 in human breast cancer. , 2009, Cancer research.

[16]  E. Ng,et al.  Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening , 2009, Gut.

[17]  C. Croce,et al.  Micro-RNAs in gastrointestinal and liver disease. , 2008, Gastroenterology.

[18]  Vassilis Georgoulias,et al.  Prognostic value of mature microRNA-21 and microRNA-205 overexpression in non-small cell lung cancer by quantitative real-time RT-PCR. , 2008, Clinical chemistry.

[19]  X. Chen,et al.  Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases , 2008, Cell Research.

[20]  J. Huh,et al.  Selection of internal reference genes for SYBR green qRT-PCR studies of rhesus monkey (Macaca mulatta) tissues , 2008, BMC Molecular Biology.

[21]  Mihaela Zavolan,et al.  Elevated expression of the miR-17-92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype. , 2008, The American journal of pathology.

[22]  Daniel B. Martin,et al.  Circulating microRNAs as stable blood-based markers for cancer detection , 2008, Proceedings of the National Academy of Sciences.

[23]  Nathalie Wong,et al.  MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. , 2008, Gastroenterology.

[24]  A. Harris,et al.  Detection of elevated levels of tumour‐associated microRNAs in serum of patients with diffuse large B‐cell lymphoma , 2008, British journal of haematology.

[25]  Laura Pelletier,et al.  MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations , 2008, Hepatology.

[26]  A. Munnich,et al.  miR-122, a paradigm for the role of microRNAs in the liver. , 2008, Journal of hepatology.

[27]  George A Calin,et al.  MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. , 2008, JAMA.

[28]  Thomas D. Schmittgen,et al.  Association of MicroRNA Expression in Hepatocellular Carcinomas with Hepatitis Infection, Cirrhosis, and Patient Survival , 2008, Clinical Cancer Research.

[29]  H. Otu,et al.  Serum Proteomics and Biomarkers in Hepatocellular Carcinoma and Chronic Liver Disease , 2008, Clinical Cancer Research.

[30]  P. Schirmacher,et al.  MicroRNA gene expression profile of hepatitis C virus–associated hepatocellular carcinoma , 2007, Hepatology.

[31]  K. Ghoshal,et al.  MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. , 2007, Gastroenterology.

[32]  Xianjun Wang,et al.  Detection of let-7a microRNA by real-time PCR in gastric carcinoma. , 2007, World journal of gastroenterology.

[33]  Miao Sun,et al.  MicroRNA and cancer: Current status and prospective , 2006, International journal of cancer.

[34]  K. Ghoshal,et al.  Downregulation of miR‐122 in the rodent and human hepatocellular carcinomas , 2006, Journal of cellular biochemistry.

[35]  T. Okanoue,et al.  Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues , 2006, Oncogene.

[36]  C. Croce,et al.  MicroRNA gene expression deregulation in human breast cancer. , 2005, Cancer research.

[37]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[38]  C. Sander,et al.  miR-122, a Mammalian Liver-Specific microRNA, is Processed from hcr mRNA and MayDownregulate the High Affinity Cationic Amino Acid Transporter CAT-1 , 2004, RNA biology.

[39]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[40]  Kang Li,et al.  Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction. , 2010, Biochemical and biophysical research communications.

[41]  Hansjuerg Alder,et al.  The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. , 2009, Gynecologic oncology.