Diagnostic Value of Serum miR-182, miR-183, miR-210, and miR-126 Levels in Patients with Early-Stage Non-Small Cell Lung Cancer

Blood-circulating miRNAs could be useful as a biomarker to detect lung cancer early. We investigated the serum levels of four different miRNAs in patients with non-small cell lung cancer (NSCLC) and assessed their diagnostic value for NSCLC. Serum samples from 112 NSCLC patients and 104 controls (20 current smokers without lung cancer, 23 pneumonia patients, 21 gastric cancer patients, and 40 healthy controls) were subjected to Taqman probe-based quantitative reverse transcription–polymerase chain reaction (RT-PCR). The data showed that the serum levels of miR-182, miR-183, and miR-210 were significantly upregulated and that the miR-126 level was significantly downregulated in NSCLC patients, compared with the healthy controls. Further receiver operating characteristic (ROC) curve analysis revealed that the serum miR-182, miR-183, miR-210, or miR-126 level could serve as a diagnostic biomarker for NSCLC early detection, with a high sensitivity and specificity. The combination of these four miRNAs with carcinoembryonic antigen (CEA) further increased the diagnostic value, with an area under the curve (AUC) of 0.965 (sensitivity, 81.3%; specificity, 100.0%; and accuracy, 90.8%) using logistic regression model analysis. In addition, the relative levels of serum miR-182, miR-183, miR-210, and miR-126 could distinguish NSCLC or early-stage NSCLC from current tobacco smokers without lung cancer and pneumonia or gastric cancer patients with a high sensitivity and specificity. Data from the current study validated that the four serum miRNAs could serve as a tumor biomarker for NSCLC early diagnosis.

[1]  Subbaya Subramanian,et al.  MicroRNA miR-183 functions as an oncogene by targeting the transcription factor EGR1 and promoting tumor cell migration. , 2010, Cancer research.

[2]  X. Chen,et al.  Identification of ten serum microRNAs from a genome‐wide serum microRNA expression profile as novel noninvasive biomarkers for nonsmall cell lung cancer diagnosis , 2011, International journal of cancer.

[3]  Sunita Ghosh,et al.  Sputum microRNA profiling: a novel approach for the early detection of non-small cell lung cancer. , 2012, Clinical and investigative medicine. Medecine clinique et experimentale.

[4]  X. Liu,et al.  Overexpression of members of the microRNA-183 family is a risk factor for lung cancer: A case control study , 2011, BMC Cancer.

[5]  Kenji Eguchi,et al.  A Japanese Lung Cancer Registry Study: Prognosis of 13,010 Resected Lung Cancers , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[6]  Wei Li,et al.  Identification and Validation of Reference Genes for qPCR Detection of Serum microRNAs in Colorectal Adenocarcinoma Patients , 2013, PloS one.

[7]  G. Yousef,et al.  Clinical evaluation of microRNA expression profiling in non small cell lung cancer. , 2013, Lung cancer.

[8]  Renato Martins,et al.  Non-small cell lung cancer, version 1.2015. , 2014, Journal of the National Comprehensive Cancer Network : JNCCN.

[9]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[10]  O. Shaker,et al.  Differential MicroRNAs Expression in Serum of Patients with Lung Cancer, Pulmonary Tuberculosis, and Pneumonia , 2013, Cell Biochemistry and Biophysics.

[11]  D. Shen,et al.  A cluster of specified microRNAs in peripheral blood as biomarkers for metastatic non-small-cell lung cancer by stem-loop RT-PCR , 2011, Journal of Cancer Research and Clinical Oncology.

[12]  Weihua Xu,et al.  High serum miR-183 level is associated with the bioactivity of macrophage derived from tuberculosis patients. , 2015, International journal of clinical and experimental pathology.

[13]  T. Dønnem,et al.  Independent and tissue‐specific prognostic impact of miR‐126 in nonsmall cell lung cancer , 2011, Cancer.

[14]  ' s report Title : Btbd 7 Contributes to reduced E-cadherin expression and Predicts Poor Prognosis in Non-small Cell Lung Cancer Version : 1 , 2022 .

[15]  M. Orringer,et al.  Gastric Cancer, Version 2.2013 , 2013 .

[16]  Z. Wang,et al.  Human miR‐1228 as a stable endogenous control for the quantification of circulating microRNAs in cancer patients , 2014, International journal of cancer.

[17]  X. Liu,et al.  Expression of miR-29c, miR-93, and miR-429 as Potential Biomarkers for Detection of Early Stage Non-Small Lung Cancer , 2014, PloS one.

[18]  Li-ping Chen,et al.  Overexpression of miR-210 is Associated with Poor Prognosis of Acute Myeloid Leukemia , 2015, Medical science monitor : international medical journal of experimental and clinical research.

[19]  P. Korošec,et al.  let-7b and miR-126 Are Down-Regulated in Tumor Tissue and Correlate with Microvessel Density and Survival Outcomes in Non–Small–Cell Lung Cancer , 2012, PloS one.

[20]  D. Tang,et al.  Identification of plasma microRNAs as novel noninvasive biomarkers for early detection of lung cancer , 2013, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[21]  J. Rathmell,et al.  Results of the two incidence screenings in the National Lung Screening Trial. , 2013, The New England journal of medicine.

[22]  A. Schetter,et al.  Circulating micro‐RNA expression profiles in early stage nonsmall cell lung cancer , 2012, International journal of cancer.

[23]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[24]  D. Welch,et al.  Breast cancer metastasis suppressor-1 promoter methylation in cell-free DNA provides prognostic information in non-small cell lung cancer , 2014, British Journal of Cancer.

[25]  Jian Gu,et al.  Quantification of preeclampsia-related microRNAs in maternal serum. , 2015, Biomedical reports.

[26]  C. Bai,et al.  Early Detection of Lung Cancer in Serum by a Panel of MicroRNA Biomarkers. , 2015, Clinical lung cancer.

[27]  Xiao-guang Liu,et al.  Differential Expression of miR-125a-5p and let-7e Predicts the Progression and Prognosis of Non-Small Cell Lung Cancer , 2014, Cancer investigation.

[28]  Lin Chen,et al.  Serum miR-182 and miR-331-3p as diagnostic and prognostic markers in patients with hepatocellular carcinoma , 2015, Tumor Biology.

[29]  Xin Huang,et al.  MiR-210--micromanager of the hypoxia pathway. , 2010, Trends in molecular medicine.

[30]  N. Girard,et al.  Noninvasive Diagnosis of Actionable Mutations by Deep Sequencing of Circulating Free DNA in Lung Cancer from Never-Smokers: A Proof-of-Concept Study from BioCAST/IFCT-1002 , 2014, Clinical Cancer Research.

[31]  Wun-Jae Kim,et al.  Downregulation of cell‐free miR‐198 as a diagnostic biomarker for lung adenocarcinoma‐associated malignant pleural effusion , 2013, International journal of cancer.

[32]  Y. Gao,et al.  Factors influencing circulating MicroRNA level in the studies of hepatocellular carcinoma biomarker. , 2015, Neoplasma.

[33]  E. DeLong,et al.  Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. , 1988, Biometrics.

[34]  Xiao-guang Liu,et al.  Evaluation of dynamic change of serum miR-21 and miR-24 in pre- and post-operative lung carcinoma patients , 2012, Medical Oncology.

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

[36]  Yong Wang,et al.  Plasma microRNAs as novel biomarkers for early detection of lung cancer. , 2011, International journal of clinical and experimental pathology.

[37]  S. Xie,et al.  Higher expression of circulating miR-182 as a novel biomarker for breast cancer , 2013, Oncology letters.

[38]  J. Neuzil,et al.  Clinical significance of circulating miR-126 quantification in malignant mesothelioma patients. , 2012, Clinical biochemistry.

[39]  J. Steen,et al.  Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma , 2012, Acta Neuropathologica.

[40]  E. Richardsen,et al.  Positive prognostic impact of miR-210 in non-small cell lung cancer. , 2014, Lung cancer.

[41]  M. Orringer,et al.  Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines. , 2013, Journal of the National Comprehensive Cancer Network : JNCCN.

[42]  Feng Jiang,et al.  Plasma microRNAs as potential biomarkers for non-small-cell lung cancer , 2010, Laboratory Investigation.

[43]  Qinghe Zhang,et al.  Meta-analysis of microRNA-183 family expression in human cancer studies comparing cancer tissues with noncancerous tissues. , 2013, Gene.

[44]  Muneesh Tewari,et al.  Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). , 2010, Methods.

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

[46]  G. Nuovo,et al.  MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines. , 2008, Biochemical and biophysical research communications.

[47]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[48]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[49]  O. Slabý,et al.  Combination of MiR-378 and MiR-210 Serum Levels Enables Sensitive Detection of Renal Cell Carcinoma , 2015, International journal of molecular sciences.

[50]  Guixi Zheng,et al.  Serum miR-210 Contributes to Tumor Detection, Stage Prediction and Dynamic Surveillance in Patients with Bladder Cancer , 2015, PloS one.