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Lung cancer is one of the deadliest cancers, in which non-small cell lung cancer (NSCLC) accounting for 85% and has a low survival rate of 5 years. Dysregulation of microRNAs (miRNAs) can participate in tumor regulation and many major diseases. In this study, we found that miR-199a-3p/5p were down-expressed in NSCLC tissue samples, cell lines, and the patient sample database. MiR-199a-3p/5p overexpression could significantly suppress cell proliferation, migration ability and promote apoptosis. Through software prediction, ras homolog enriched in brain (Rheb) was identified as a common target of miR-199a-3p and miR-199a-5p, which participated in regulating mTOR signaling pathway. The same effect of inhibiting NSCLC appeared after down-regulating the expression of Rheb. Furthermore, our findings revealed that miR-199a can significantly inhibit tumor growth and metastasis

Non-small cell lung cancer (NSCLC) is the most common form of cancer, resulting in cancer-related deaths worldwide. Exosomes, a subclass of extracellular vesicles, are produced and secreted from various types of cells, including cancer cells. Cancer-derived exosomes can deliver nucleic acids, proteins, and lipids to provide a favorable microenvironment that supports tumor growth through enhancing cell proliferation and metastasis. Our results showed that miR-224-5p was upregulated in NSCLC patient tissues and cell lines, with a tumor-promoting phenotype. Meanwhile, exosome-derived miR-224-5p induced cell proliferation and metastasis in NSCLC and human lung cells. Moreover, we characterized the androgen receptor (AR) as a direct target of miR-224-5p. Tumor xenograft assay experiments revealed that overexpression of miR-224-5p drove NSCLC tumor growth via the suppression of AR and the mediation of epithelial-mesenchymal transition (EMT). Collectively, our results suggest that miR-224-5p-enriched exosomes promote tumorigenesis by directly targeting AR in NSCLC, which may provide novel potential therapeutic and preventive targets for NSCLC., Graphical Abstract, Exosomes and microRNAs play important roles in tumorigenesis. In non-small lung cancer, the cancer-derived exosome miR-224-5p increased significantly. With exosomes transporting, miR-224-5p promoted the proliferation and metastasis ability of their receptor cells via targeting androgenic receptor. Consequently, exosomal miR-224-5p may have a promising prospect in lung cancer therapy.

Lung cancer is acknowledged as a common cancer with high morbidity and mortality. MicroRNAs (miRNAs), kind of non-coding single-stranded RNA molecules, can be used in cancer clinical treatments. In this research, miR-199a-5p was seen lowly expressed in NSCLC sera samples. miR-199a-5p suppressed the cell proliferation, migration and arrested cell cycle in NSCLC cell lines. The results showed that SLC2A1 (glucose transporter 1, GLUT1) was a direct target of miR-199a-5p. Downregulation of SLC2A1 could not only inhibit cell proliferation, migration and cell cycle, but also promote cell apoptosis. The data suggests that miR-199a-5p can inhibit glucose metabolism in NSCLC by targeting SLC2A1.This study proves that miR-199a-5p / SLC2A1 can play an essential role in the development of NSCLC by targeting SLC2A1. It puts forward a new approach for clinical treatments of NSCLC.

Background Histology is a traditional way to classify subtypes of thymoma, because of low cost and convenience. Yet, due to the diverse morphology of thymoma, this method increases the complexity of histopathologic classification, and requires experienced experts to perform correct diagnosis. Therefore, in this study, we developed an alternative method by identifying protein biomarkers in order to assist clinical practitioners to make right classification of thymoma subtypes. Methods In total, 204 differentially expressed proteins in three subtypes of thymoma, AB, B2, and B3, were identified using mass spectrometry. Pathway analysis showed that the differentially expressed proteins in the three subtypes were involved in activation-related, signaling transduction-related and complement system-related pathways. To predict the subtypes of thymoma using the identified protein signatures, a support vector machine algorithm was used. Leave-one-out cross validation methods and receiver operating characteristic analysis were used to evaluate the predictive performance. Results The mean accuracy rates were > 80% and areas under the curve were ≧0.93 across these three subtypes. Especially, subtype B3 had the highest accuracy rate (96%) and subtype AB had the greatest area under the curve (0.99). One of the differentially expressed proteins COL17A2 was further validated using immunohistochemistry. Conclusions In summary, we identified specific protein signatures for accurately classifying subtypes of thymoma, which could facilitate accurate diagnosis of thymoma patients.

Group 2 innate lymphoid cells (ILC2s) manifest tissue heterogeneity and are crucial modulators of regional immune responses. The molecular mechanisms regulating tissue ILC2 properties remain elusive. Here, we interrogate the signatures of ILC2s from five tissues at the transcriptome and epigenetic level. We have found that tissue microenvironment strongly shapes ILC2 identities. The intestine induces Aiolos+ILC2s, whereas lung and pancreas enhance Galectin-1+ILC2s. Though being a faithful gut ILC2 feature under the steady state, Aiolos is induced in non-intestinal ILC2s by pro-inflammatory cytokines. Specifically, IL-33 stimulates Aiolos expression in both human and mouse non-intestinal ILC2s. Functionally, Aiolos facilitates eosinophil recruitment by supporting IL-5 production and proliferation of ST2+ILC2s through inhibiting PD-1. At the epigenetic level, ILC2 tissue characters are imprinted by open chromatin regions (OCRs) at non-promoters. Intestinal-specific transcription factor aryl hydrocarbon receptor (Ahr) binds to Ikzf3 (encoding Aiolos) locus, increases the accessibility of an intestinal ILC2-specific OCR, and promotes the Ikzf3 transcription by enhancing H3K27ac. Consequently, Ahr prevents ILC2s entering an "exhausted-like" state through sustaining Aiolos expression. Our work elucidates mechanism of ILC2 tissue adaptation and highlights Aiolos as a potential target of type 2 inflammation.

The 5-year survival rate of lung cancer is one of the lowest among various malignant tumors. Long noncoding RNAs (lncRNAs), noncoding RNAs longer than 200 nucleotides, can function either as tumor suppressors or as oncogenes. The aim of this study is to investigate the function of lncRNA LINC01296 and its molecular mechanism in non-small-cell lung cancer (NSCLC). According to the Gene Expression Omnibus database, 10 differentially expressed lncRNAs in NSCLC cells and patient tissues are upregulated. LINC01296 is the one with the most significant overexpression. Knockdown of LINC01296 inhibits the growth and migration, arrests the cell cycle, and promotes the apoptosis of NSCLC cells. Knocking down LINC01296 in vivo suppresses tumor growth and metastasis. LINC01296 also acts as the sponge of miR-143-3p. Lowering the expression of LINC01296 leads to decreased expression of autophagy-related 2B (ATG2B), a target gene of miR-143-3p. Moreover, downregulation of LINC01296 promotes paclitaxel sensitivity in NSCLC. These results demonstrated that the LINC01296/miR-143-3p/ATG2B axis is crucial in promoting the development of NSCLC and paclitaxel resistance. Our study may provide new ideas for the further research of clinical chemotherapy of NSCLC in the near future.

Epidermal growth factor receptor (EGFR), a cancer-driven gene, plays an important role in tumorigenesis of lung cancer. Cryptotanshinone (CT) is the main constituent of salia miltiorrhiza and has been found to affect tumor progression. However, the mechanism of CT on lung cancer is still not clear. Here we found that CT could suppress the proliferation of non-small cell lung cancer (NSCLC) by inhibiting EGFR. We further confirmed that knockdown of EGFR also suppressed cell proliferation and arrested cell cycle progression. Furthermore, we evaluated EGFR was a direct target gene of miR-146a-5p which was upregulated by CT. In general, our results proved that CT could restrain NSCLC via miR-146a-5p/EGFR axis. CT and miR-146a-5p have the potential to be positive candidates in drug development of NSCLC.

tRNA-derived RNA fragments (tRFs), non-coding single-stranded RNAs with 14-35 nt in length, were found to play important roles in gene regulation, even in carcinogenesis. In this study, we investigated the expression of tRF-Leu-CAG in human non-small cell lung cancer (NSCLC) and its function in the cell proliferation and cell cycle of NSCLC. The expression level of tRF-Leu-CAG was detected in NSCLC tissues, cell lines, and sera. tRF-Leu-CAG RNA levels were higher in NSCLC tumor tissues than in normal tissues, and also upregulated in NSCLC cell lines. A significant relationship was observed between stage progression and tRF-Leu-CAG in NSCLC sera. We found that in H1299 cells, inhibition of tRF-Leu-CAG suppressed cell proliferation and impeded cell cycle. AURKA was also repressed with the knockdown of tRF-Leu-CAG. Thus, our study revealed that tRF-Leu-CAG may be involved in regulating AURKA and could be a new diagnostic marker and potential therapeutic target in NSCLC.

Lung cancer is one of the most malignant tumors that can form in the human. MicroRNAs (MiRNAs) play significant role in tumor progression. Human lung cancer tissues and cell lines were used to determine miR-150-5p respectively, and Liver Kinase B1 (LKB1) expression using quantitative real-time PCR (qRT-PCR). The data analysis website Kaplan-Meier Plotter (database obtained from The Cancer Genome Atlas) was used to perform a survival analysis with LKB1 levels. Using the appropriate assays, the function of miR-150-5p was also detected in cellular proliferation, migration and cell apoptosis as well as cell cycle. Results revealed that miR-150-5p was upregulated in non-small cell lung cancer (NSCLC) tissue and cell lines. In NSCLC, miR-150-5p promoted cellular proliferation and migration, but decreased cellular apoptosis. Conversely, miR-150-5p inhibition suppressed cellular growth. These results further revealed a network of cellular signaling for miR-150-5p to target LKB1. Ectopic expression of LKB1 can mitigate the tumor-promoting function of miR-150-5p. Collectively, these results indicated that miR-150-5p may promote lung cancer by inhibiting the suppressor gene LKB1 in NSCLC.

MicroRNAs are a class of non-coding single-stranded RNA, 20-23 nucleotide in length, which can be involved in the regulation of gene expression. Through binding with 3'-untranslated regions (3'-UTR), microRNAs can cause degradation of target mRNAs or inhibition of translation, and thus regulating the expression of genes at the post-transcriptional level. In this study, we found that miR-486-5p was significantly downregulated in non-small cell lung cancer (NSCLC) tissues and cell lines, suggesting that miR-486-5p might function as a tumor suppressor in lung cancer. Additionally, we showed that CDK4, an oncogene that plays an important role in cell cycle G1/S phase progression, was directly targeted by miR-486-5p. Furthermore, our data reveals that knockdown of CDK4 by siRNA can inhibit cell proliferation, promote apoptosis, and impede cell-cycle progression. In epigenetics, the upstream promoter of miR-486-5p was strongly regulated by methylation in NSCLC. Collectively, our results suggest that miR-486-5p could not only inhibit NSCLC by downregulating the expression of CDK4, but also be as a promising and potent therapy in the near future.

Lung cancer is one of the most common malignant diseases globally, composed of non-small cell lung cancer (NSCLC, 85%) and small cell lung cancer (SCLC, 15%). MicroRNAs (miRNAs) are single-stranded noncoding RNAs having important roles in lung cancer development. miR-411-5p/3p were reported to be increased significantly in human NSCLC tissues and cell lines. Moreover, miR-411-5p/3p overexpression could accelerate cell proliferation and migration, and impede cell apoptosis in NSCLC cell lines. Mechanically, SPRY4 is confirmed a direct target of miR-411-5p/3p. Furthermore, our findings showed that miR-411-5p/3p promoted lung tumor growth in vivo, decreased SPRY4 expression dramatically, and induced EGFR, AKT signaling activation, as well as epithelial-mesenchymal transition (EMT) simultaneously in tumor tissues. In addition, we showed that miR-411-5p also targeted tumor suppressor TXNIP, involved in regulating positively cell cycle progress in SPC-A1 cells rather than in H1299. Whether cell specificity of low TXNIP mRNA level in H1299 is responsible for the different response to cell cycle between H1299 and SPC-A1 would need further explorations. Collectively, these results suggest that miR-411-5p/3p are required for NSCLC development by suppressing SPRY4 and TXNIP; thus, the miR-411-SPRY4-AKT axis might act as a promising target for lung cancer therapy clinically.

Dysregulated microRNAs (miRNAs) have an important role in many malignant tumors. However, elucidating the roles of miRNAs in cancer biology, especially in epithelial cancers, remains an ongoing process. In this study, we show that both miR-143 and miR-145, which belong to the same miRNA cluster, can negatively modulate expression of their target gene, MDM2. The miR-143 and miR-145 is posttranscriptionally activated by upregulated p53, thereby generating a short miRNAs-MDM2-p53 feedback loop. Re-expression of these miRNAs suppresses cellular growth and triggers the apoptosis of epithelial cancer, in vitro and in vivo, by enhancing p53 activity via MDM2 turnover. Moreover, the miRNA-dependent MDM2 turnover contributes to the equilibrium of repeated p53 pulses in response to DNA damage stress. These findings suggest that MDM2 dysregulation caused by downregulation of miR-143 and miR-145 contributes to epithelial cancer development and has a key role in regulating cellular proliferation and apoptosis. Re-expression of miR-143 and miR-145 may be a reasonable strategy for treatment of epithelial cancers.

Paired box gene 4 (PAX4) is a transcriptional modulator located on chromosome 7q32, and its expression is dysregulated in a variety of human cancers, suggesting that PAX4 may be important in multiple tumors as a driver gene. Here, we show that PAX4 promoted migration and invasion in human epithelial cancers by decreasing miR-144 and miR-451 (miR-144/451) expression levels. Accordingly, miR-144/451 suppressed the migratory and invasive phenotypes, even in PAX4-expressing cells. Mechanistically, miR-144/451 inhibits cancer metastasis by targeting the A disintegrin and metalloproteinase (ADAM) protein family members ADAMTS5 and ADAM10. Their dysregulation is associated with increased tumor invasiveness and metastasis, then reduced patient prognosis in certain epithelial cancers. This discovery suggests that a PAX4-miR-144/451-ADAMs axis regulates human epithelial cancer metastasis, thus opening up therapeutic possibilities and predicting prognosis for those cancer types.

Paclitaxol (PTX) resistance is one of main factors which affect the outcome of chemotherapy of lung adenocarcinoma. The aim of this study is to compare the secreted protein expression profiles between Paclitaxol (PTX) resistant and sensitive lung adenocarcinoma cells by proteomic research method, so as to provide evidence of choosing individual chemotherapy drugs in clinical treatment.Total secreted proteins extracted from a PTX sensitive cell line A549 and a PTX resistant cell line A549-Taxol were separated by fluorscent differential gel electrophoresis (DIGE). High quality 2-DE profiles were obtained and analyzed by Decyder 6.5 analysis software to screen differentially expressed protein spots. Those spots were identified by mass spectrometry.2-DE patterns of lung adenocarcinoma cells with high-resolution and reproducibility were obtained. 76 significantly differentially expressed protein spots were screened, 19 proteins were identified by mass spectrometry. The identified proteins could be classified into different catogories: metabolic enzyme, extracellular matrix (ECM) degradation enzyme, cytokine, signal transducer, cell adhesion, and so on.Multiple secreted proteins related to chemoresistance of A549-Taxol cells were identified in this study for the first time. The results presented here would provide clues to identify new serologic chemoresistant biomarkers of NSCLC.