| Lung cancer is the first leading cause of cancer-related death and the most frequently diagnosed cancer worldwide. This high mortality rate is usually ascribed to late diagnosis. Despite significant advances in the diagnosis, staging and treatment of lung cancer in recent decades, few significant improvements in overall survival have been achieved:the5-year overall survival rate remains16%. Hence, a top priority in lung cancer research should be the identification of a diagnostic method with high sensitivity and specificity.We recently conducted proteomics analysis in12pairs of lung squamous cell tumors and their corresponding normal tissues. Two-dimensional fluorescence difference gel electrophoresis and subsequent MALDI-TOF/TOF mass spectrometry were performed to identify proteins differentially expressed. A total of28nonredundant proteins were identified with significant alteration in lung tumors. We reported the up-regulation of isocitrate dehydrogenase1(IDH1), superoxide dismutase2(SOD2),14-3-3ε, and receptor of activated protein kinase C1(RACK1) and the down-regulation of peroxiredoxin2(PRDX2). This was the first report that IDH1is upregulated in lung cancer tissues. IDH1normally localizes to the cytoplasm and peroxisomes, catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate, producing the reduced form of nicotinamide-adenine dinucleotide phosphate (NADPH).In this study, the regulation of IDH1, SOD2,14-3-3ε, RACK1, and PRDX2were validated by RT-PCR and Western blot analysis in independent15pairs of samples. Increased IDH1expression was further verified by the immunohistochemical study in extended73squamous cell carcinoma and64adenocarcinoma clinical samples. A correlation between IDH1expression and poor overall survival of non-small cell lung cancer (NSCLC) patients was observed. Furthermore, knockdown of IDH1by RNA interference suppressed the proliferation of NSCLC cell line and decreased the growth of xenograft tumors in vivo. In addition, ELISA analysis in small sample showed that the plasma level of IDH1was significantly elevated in NSCLC patients compared with benign lung disease patients and healthy individuals. These observations suggested that IDH1, as a protein promoting tumor growth, could be used as a histochemical biomarker for prognosis prediction and a potential plasma biomarker for the diagnosis of NSCLC. Then we conducted a study aimed to examine the plasma levels of IDH1in a large patient population to evaluate its effectiveness in NSCLC diagnosis. The plasma levels of IDH1, CA125, Cyfra21-1, and CEA were assayed by ELISA and ECLIA. Blood samples were obtained from1,422participants (943patients with NSCLC and479healthy controls). The samples were randomly divided into a training set and a test set. Receiver operating characteristic and binary logistic regression analyses were applied to evaluate diagnostic efficacy and establish diagnostic mathematical models. Plasma IDH1levels were significantly higher in patients with NSCLCs than in healthy controls (p<0.001). The diagnostic use of IDH1in lung adenocarcinoma was significantly greater than that of CA125, Cyfra21-1, or CEA (p<0.001). The model combining IDH1with CEA, CA125, and Cyfra21-1was more effective for lung adenocarcinoma diagnosis than IDH1alone. In addition, the plasma levels of IDH1could contribute to the diagnostic model of lung squamous cell carcinoma.In conclusion, our findings demonstrated that IDH1were significantly upregulated in lung cancer cell lines and clinical samples and that this increased expression was associated with the patient prognosis. The upregulation of IDH1might play an important role in proliferation in lung cancer. And most important of all, IDH1can be used as a plasma biomarker for the diagnosis of NSCLC, particularly lung adenocarcinoma, with relatively high sensitivity and specificity. |
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