During epithelial-mesenchymal transition (EMT) epithelial cancer cells transdifferentiate into highly motile, invasive, mesenchymal-like cells, giving rise to disseminating tumor cells. Few of these disseminated cells successfully metastasize. Immune cells and inflammation in the tumor microenvironment were shown to drive EMT, but few studies investigated the consequences of EMT for tumor immunosurveillance. In addition to initiating metastasis, we demonstrate that EMT confers increased susceptibility to natural killer (NK) cells and contributes, in part, to the inefficiency of the metastatic process. Depletion of NK cells allowed spontaneous metastasis without affecting primary tumor growth. EMT-induced modulation of E-cadherin and cell adhesion molecule 1 (CADM1) mediated increased susceptibility to NK cytotoxicity. Higher CADM1 expression correlates with improved patient survival in 2 lung and 1 breast adenocarcinoma patient cohorts and decreased metastasis. Our observations reveal a novel NK-mediated, metastasis-specific immunosurveillance in lung cancer and present a window of opportunity for preventing metastasis by boosting NK cell activity.

Background: Currently, no satisfactory biomarkers are available to screen for lung cancer. Surface-Enhanced Laser Desorption/ionization Time-of- Flight Mass Spectrometry ProteinChip system (SELDI-TOF-MS) is one of the currently used techniques to identify biomarkers for cancers. The aim of this study is to explore the application of serum SELDI proteomic patterns to distinguish lung cancer patients from healthy individuals. Methods: A total of 208 serum samples, including 158 lung cancer patients and 50 healthy individuals, were randomly divided into a training set (including 11 sera from patients with stages I/II lung cancer, 63 from patients with stages III/IV lung cancer and 20 from healthy controls) and a blinded test set (including 43 sera from patients with stages I/II lung cancer, 41 from patients with stages III/IV lung cancer and 30 from healthy controls). All samples were analyzed by SELDI technology. The spectra were generated on weak cation exchange (WCX2) chips, and protein peaks clustering and classification analyses were made using Ciphergen Biomarker Wizard and Biomarker Pattern software, respectively. We additionally determined Cyfra21-1 and NSE in the 208 serum samples included in this study using an electrochemiluminescent immunoassay. Results: Five protein peaks at 11493, 6429, 8245, 5335 and 2538 Da were automatically chosen as a biomarker pattern in the training set. When the SELDI marker pattern was tested with the blinded test set, it yielded a sensitivity of 86.9%, a specificity of 80.0% and a positive predictive value of 92.4%. The sensitivities provided by Cyfra21-1 and NSE used individually or in combination were significantly lower than that of the SELDI marker pattern (P < 0.005 or 0.05, respectively). Based on the results of the test set, we found that the SELDI marker pattern showed a sensitivity of 91.4% in the detection of non-small cell lung cancers (NSCLC), which was significantly higher than that in the detection of small cell lung cancers (P < 0.05); The pattern also had a sensitivity of 79.1% in the detection of lung cancers in stages I/II. Conclusion: These results suggest that serum SELDI protein profiling can distinguish lung cancer patients, especially NSCLC patients, from normal subjects with relatively high sensitivity and specificity, and the SELDI-TOF-MS is a potential tool for the screening of lung cancer.

The long noncoding RNA (lncRNA) MIR22HG has previously been identified as a prognostic marker in hepatocellular carcinoma. Here, we performed a comprehensive analysis of lncRNA expression profiles from RNA-Seq data and report that MIR22HG plays a similar role in lung cancer. Analysis of 918 lung cancer and normal lung tissues and lung cancer cell lines revealed that MIR22HG was significantly downregulated in lung cancer; this decreased expression was associated with poor patient survival. MIR22HG bound and stabilized the YBX1 protein. Silencing of MIR22HG triggered both cell survival and cell death signaling through dysregulation of the oncogenes YBX1, MET, and p21. In this MIR22HG network, p21 played an oncogenic role by promoting cell proliferation and antiapoptosis in lung cancers. MIR22HG played a tumor-suppressive role as indicated by inhibition of multiple cell cycle–related genes in human primary lung tumors. These data show that MIR22HG has potential as a new diagnostic and prognostic marker and as a therapeutic target for lung cancer. Significance: The lncRNA MIR22HG functions as a tumor suppressor, with potential use a diagnostic/prognostic marker and therapeutic target in lung cancer. Cancer Res; 78(12); 3207–19. ©2018 AACR.

The aim of this study was to identify differentially-expressed miRNAs in the serum of non-small cell lung cancer (NSCLC) patients that might be a clinically-useful tool for lung cancer early detection. We performed miRNA expression profile analysis using TaqMan OpenArray Human panel in a discovery set of 70 serum samples obtained at lung tumor resection and 22 non-cancer subjects (NC). Selected serum miRNAs were then validated by quantitative PCR using an independent validation set of serum samples from LC patients (n = 84) and NC (n = 23). Sixty miRNAs were significantly up-regulated and 31 were down-regulated in the serum from NSCLC patients versus NC (adjusted p < 0.001). Four miRNAs (miR-193b, miR-301, miR-141 and miR-200b) were selected for validating their diagnostic value in an independent cohort. In the discovery set, the ROC plot derived from the combination of these miRNAs yielded an area under the curve (AUC) of 0.985 (95% CI 0.961–1.000, p < 0.001). In the test set, this miRNA signature exhibited an AUC of 0.993 (95% CI 0.979–1.000, p < 0.001). In conclusion, we identified a serum 4-miRNA signature that discriminated with high accuracy lung cancer patients from NC. Further prospective validation of this miRNA signature is warranted.

Purpose: The microRNA-34b/c (miR-34b/c) is considered a tumor suppressor in different tumor types and a transcriptional target of TP53. The main objectives of this study were to investigate the clinical implications of miR-34b/c methylation in patients with early-stage lung adenocarcinoma and to determine the functional role of miR-34b/c re-expression in lung adenocarcinoma cell lines. Experimental Design: Aberrant methylation and expression of miR-34b/c were assessed in 15 lung adenocarcinoma cell lines and a cohort of 140 early-stage lung adenocarcinoma. Lung adenocarcinoma cell lines were transfected with miR-34b/c and the effects upon cell proliferation, migration, invasion, and apoptosis were investigated. Results: Aberrant methylation of miR-34b/c was detected in 6 (40%) of 15 lung adenocarcinoma cell lines and 64 of 140 (46%) primary lung adenocarcinoma. Expression of miR-34b/c was significantly reduced in all methylated cell lines and primary tumors, especially with TP53 mutations. Patients with increased miR-34b/c methylation had significantly shorter disease-free and overall survival as compared to patients with unmethylated or low level of miR-34b/c methylation. Ectopic expression of miR-34b/c in lung adenocarcinoma cell lines decreased cell proliferation, migration, and invasion. Conclusions: Epigenetic inactivation of miR-34b/c by DNA methylation has independent prognostic value in patients with early-stage lung adenocarcinoma. Reexpression of miR-34b/c leads to a less aggressive phenotype in lung adenocarcinoma cell lines. Clin Cancer Res; 19(24); 6842–52. ©2013 AACR.

Non-coding RNA LINC00857 is predictive of poor patient survival and promotes tumor progression via cell cycle regulation in lung cancer Non-coding RNA LINC00857 is predictive of poor patient survival and promotes tumor progression via cell cycle regulation in lung cancer