Serum exosome tRFs as a promising biomarker for active tuberculosis and latent tuberculosis infection.

OBJECTIVE: To analyse the expression profiles of serum exosome tRFs/tiRNAs and to explore their diagnostic value in tuberculosis (TB) activity. METHODS: The serum exosome tRF/tiRNA profile was analysed using high-throughput sequencing technology in 5 active tuberculosis (ATB) patients, 5 latent tuberculosis infection (LTBI) patients and 5 healthy controls (HCs). Then, serum exosome tRFs/tiRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR), and their diagnostic value was evaluated by receiver operating characteristic curve (ROC) and area under the curve (AUC). Finally, bioinformatics analysis was performed to explore and identify the potential biological pathways induced by tRFs/tiRNAs. RESULTS: The sequencing results revealed that serum exosome tRF/tiRNA expression profiles were different among ATB patients, LTBI patients and HCs. Three tRFs (tRF-56:75-Trp-CCA-4, tRF-1:22-chrM.Ser-GCT and tRF-56:76-Val-TAC-1-M2) were selected for qRT-PCR validation. The results demonstrated that the expression level of tRF-1-22-chrM.Ser-GCT was upregulated in ATB patients, while tRF-56-75-Trp-CCA-4 was downregulated, which was consistent with the sequencing data. The AUCs of tRF-56:75-Trp-CCA-4 and tRF-1:22-chrM. Ser-GCT were 0.824 and 1.000, respectively, which have significant values in the diagnosis of ATB patients. Moreover, the expression levels of tRF-56:75-Trp-CCA-4 and tRF-1:22-chrM.Ser-GCT and tRF-56:76-Val-TAC-1-M2 in ATB patients and LTBI were different, which indicated that these three tRFs could effectively distinguish ATB patients and LTBI patients. CONCLUSION: Our findings indicate that serum exosome tRFs can be used as potential markers for the diagnosis of ATB and LTBI.

The value of lung function assessment and Testin expression detection in clinicopathological features and prognosis of NSCLC patients.

OBJECTIVE: The aim of this study is to investigate the clinical value and potential prognostic significance of lung function assessment and Testin expression in non-small cell lung cancer (NSCLC) patients. METHODS: The NSCLC patients were classified into three groups according to lung function: group of normal lung function, group of PRISm (preserved ratio impaired spirometry) (FEV1, forced expiratory volume during the first second < 80% predicted and FEV1/FVC (forced vital capacity) ≥ 70%) and group of COPD (chronic obstructive pulmonary disease) (FEV1/FVC < 70%). The pre-operational clinicopathological characteristics of these patients were recorded and the markers of systemic inflammatory response, including neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and eosinophils (EOS), were compared between three groups. The expression of Testin in NSCLC samples was detected by IHC and we further explored the correlation between Testin expression and clinicopathological characteristics and prognosis of NSCLC patients. Finally, Cox regression analysis was conducted to study the prognostic factors of NSCLC patients. RESULTS: Of the 158 NSCLC patients, percentages of normal lung function, PRISm and COPD were 41.4%, 22.8% and 36.1%, respectively. Patients with tumor in the left lung were more likely to have pulmonary dysfunction (PRISm and COPD) than the right lung. The markers of systemic inflammatory response showed differences to various degree in the three groups and NSCLC patients with PRISm or COPD presented more unfavorable prognosis than patients with normal function. The expression of Testin correlated with lymph node metastasis, TNM stage and tumor invasion of NSCLC patients. Moreover, patients with low Testin expression exhibited poorer disease-free survival and overall survival than those with high Testin expression. In Cox regression analysis, we found that PRISm, COPD and Testin expression served as prognostic factors in NSCLC patients. CONCLUSIONS: The presence of COPD or PRISm influenced systemic inflammatory response and prognosis of NSCLC patients. Testin expression correlated with clinicopathological features and could be potentially used as a prognostic marker in NSCLC.

Dipeptidyl peptidase 4 inhibitor reduces tumor-associated macrophages and enhances anti-PD-L1-mediated tumor suppression in non-small cell lung cancer

Purpose The efficacy of immune checkpoint inhibitors such as programmed cell death ligand 1 (PD-L1) antibodies in non-small cell lung cancer (NSCLC) is limited, and combined use with other therapies is recommended. Dipeptidyl peptidase 4 (DPP4) inhibitors, a class of small molecule inhibitors, are highly effective for treating type 2 diabetes. Emerging evidence implicates DPP4 inhibitors as immunomodulators that modify aspects of innate and adaptive immunity. We evaluated the combination of a DPP4 inhibitor (anagliptin) and PD-L1 blockade in an NSCLC mouse model. Methods The effect of the combination of anti-PD-L1 and anagliptin was evaluated in subcutaneous mouse models of NSCLC. Tumor-infiltrating immune cells were analyzed by flow cytometry. Bone marrow-derived monocytes of C57BL/6 mice were isolated in vitro to examine the underlying mechanism of anagliptin on the differentiation and polarization of macrophage. Results Anagliptin dramatically improved the efficacy of PD-L1 antibody monotherapy by inhibiting macrophage formation and M2 polarization in the tumor microenvironment. Mechanistically, anagliptin suppressed the production of reactive oxygen species in bone marrow monocytes by inhibiting NOX1 and NOX2 expression induced by macrophage colony-stimulating factor, reduced late ERK signaling pathway activation, and inhibited monocyte-macrophage differentiation. However, the inhibitory effect was reactivated by lipopolysaccharide and interferon-gamma interacting with corresponding receptors during M1 macrophage polarization, but not M2. Conclusions Anagliptin can enhance PD-L1 blockade efficacy in NSCLC by inhibiting macrophage differentiation and M2 macrophage polarization, and combination therapy may be a promising strategy for treating PD-L1 blockade therapy-resistant patients with NSCLC (AU)

Early identification of lung cancer patients with venous thromboembolism: development and validation of a risk prediction model.

INTRODUCTION: Venous thromboembolism(VTE) is a leading cause of death in patients with lung cancer. Furthermore, hospitalization of patients with advanced lung cancer for VTE treatment represents a major economic burden on the national public health resources. Therefore, we performed this prospective study to identify clinical biomarkers for the early identification of VTE in lung cancer patients. METHODS: This prospective study enrolled 158 patients with confirmed lung cancer, including 27 who were diagnosed with VTE within six months of the follow-up after lung cancer diagnosis. Multivariate logistic regression analysis was used to evaluate the diagnostic performancese of all the relevant clinical features and laboratory indicators in identifying lung cancer patients with a higher risk of VTE. A novel risk prediction model was constructed consisting of five clinical variables with the best diagnostic performances and was validated using the receiver operation characteristic(ROC) curves. The diagnostic performances of the new risk prediction model was also compared with the Khorana risk score (KRS) and the Padua risk score (PRS). RESULTS: The VTE group of lung cancer patients (n = 27) showed significantly higher serum levels of fibrin degradation products (FDP), D-dimer, thrombomodulin (TM), thrombin-antithrombin-complex (TAT), α2-plasmin inhibitor-plasmin Complex (PIC), and tissue plasminogen activator-plasminogen activator inhibitor complex (t-PAIC) compared to those in the non-VTE group (n = 131). ROC curve analyses showed that the diagnostic efficacy of the new VTE risk prediction model with TM ≥ 9.75 TU/ml, TAT ≥ 2.25ng/ml, t-PAIC ≥ 7.35ng/ml, history of VTE, and ECOG PS score ≥ 2 was superior than the KRS and the PRS in the early identification of lung cancer patients with a higher risk of VTE. CONCLUSIONS: The new risk prediction model showed significantly high diagnostic efficacy in the early identification of lung cancer patients with a high risk of VTE. The diagnostic efficacy of the new risk prediction model was higher than the KRS and the PRS in this cohort of lung cancer patients.

Dipeptidyl peptidase 4 inhibitor reduces tumor-associated macrophages and enhances anti-PD-L1-mediated tumor suppression in non-small cell lung cancer.

PURPOSE: The efficacy of immune checkpoint inhibitors such as programmed cell death ligand 1 (PD-L1) antibodies in non-small cell lung cancer (NSCLC) is limited, and combined use with other therapies is recommended. Dipeptidyl peptidase 4 (DPP4) inhibitors, a class of small molecule inhibitors, are highly effective for treating type 2 diabetes. Emerging evidence implicates DPP4 inhibitors as immunomodulators that modify aspects of innate and adaptive immunity. We evaluated the combination of a DPP4 inhibitor (anagliptin) and PD-L1 blockade in an NSCLC mouse model. METHODS: The effect of the combination of anti-PD-L1 and anagliptin was evaluated in subcutaneous mouse models of NSCLC. Tumor-infiltrating immune cells were analyzed by flow cytometry. Bone marrow-derived monocytes of C57BL/6 mice were isolated in vitro to examine the underlying mechanism of anagliptin on the differentiation and polarization of macrophage. RESULTS: Anagliptin dramatically improved the efficacy of PD-L1 antibody monotherapy by inhibiting macrophage formation and M2 polarization in the tumor microenvironment. Mechanistically, anagliptin suppressed the production of reactive oxygen species in bone marrow monocytes by inhibiting NOX1 and NOX2 expression induced by macrophage colony-stimulating factor, reduced late ERK signaling pathway activation, and inhibited monocyte-macrophage differentiation. However, the inhibitory effect was reactivated by lipopolysaccharide and interferon-gamma interacting with corresponding receptors during M1 macrophage polarization, but not M2. CONCLUSIONS: Anagliptin can enhance PD-L1 blockade efficacy in NSCLC by inhibiting macrophage differentiation and M2 macrophage polarization, and combination therapy may be a promising strategy for treating PD-L1 blockade therapy-resistant patients with NSCLC.

MiR-504-3p Has Tumor-Suppressing Activity and Decreases IFITM1 Expression in Non-Small Cell Lung Cancer Cells.

Objective: To analyze the impact of expression of miR-504-3p on the proliferation, migration, cell cycle transit and rate of apoptosis of NSCLC cells and explore the underlying mechanisms. Methods: The Cancer Genome Atlas (TCGA) database was used to compare the expression levels of miR-504 between NSCLC tissues and normal lung tissues. NSCLC cells were transfected with lentiviral vectors that either overexpressed or knocked down miR-504-3p to evaluate its effects on NSCLC biological behavior. Quantitative Real Time Polymerase Chain Reaction was used to measure the levels of miR-504-3p and Interferon-Induced Transmembrane Protein 1 (IFITM1). A luciferase reporter array was used to reveal whether miR-504-3p directly targets IFITM1. Results: The expression of miR-504 was significantly down-regulated in lung cancer tissues compared to normal lung tissues. Overexpression of miR-504-3p in NSCLC cell lines inhibited cell proliferation, migration and promoted cell apoptosis. Meanwhile, changes in the expression level of miR-504-3p had no significant effect on NSCLC cell cycle progression. Moreover, over-expressed miR-504-3p following its transfection significantly decreased the expression of IFITM1 in NSCLC cell lines and suppressed the activity of the luciferase reporter containing wild type but not mutant IFITM1 3' -UTR. Conclusion: miR-504-3p inhibits cell proliferation and migration and promotes cell apoptosis in NSCLC cells. MiR-504-3p decreases IFITM1 expression in NSCLC cells, which may be a potential mechanism of its tumor-suppressive functions in NSCLC.

LINC00116 Is a Novel Prognostic Biomarker of Nonsmall Cell Lung Cancer.

Purpose: Lung cancer is the most malignant respiratory cancer with an undesirable prognosis. Emerging evidence shows that long noncoding RNAs (lncRNAs) can regulate lung cancer development. Currently, the role of LINC00116, a novel lncRNA, in lung cancer is unknown. This study was designed to evaluate the association and clinical significance between the level of LINC00116 and lung cancer. Materials and Methods: In the present study, 19 paired lung cancer and non-cancerous adjacent tissues were collected from lung cancer patients to measure the expression of LINC00116 by quantitative reverse transcription-polymerase chain reaction and Microarray analysis (Oncomine and CCLE). Clinicopathological features of patients were obtained to analyze their relationships with LINC00116 expression levels. Kaplan-Meier survival analysis was used to analyze the prognosis. Results: LINC00116 expression was upregulated in lung cancer. Furthermore, we found that LINC00116 expression was correlated with pT factor, pN factor, pTNM stage, smoking history, differentiation, and Ki-67 labeling index (p < 0.05). In addition, Kaplan-Meier survival analysis showed that high levels of LINC00116 expression were associated with poorer overall survival (OS), progression-free survival (PFS) and first progression (FP) (p < 0.05) of lung cancer patients. Conclusions: Our study provided evidence that LINC00116 is upregulated in lung cancer tissues and can predict poor survival. It might also be able to serve as a therapeutic target. The Clinical Trial Registration number 2022-020.

Estradiol initiates the immune escape of non-small cell lung cancer cells via ERß/SIRT1/FOXO3a/PD-L1 axis.

Mounting evidence has postulated estrogen as a contributor for lung cancer development and progression. Here, we focused on the effect of estradiol (E2) on the immune escape of non-small cell lung cancer (NSCLC). The expression of FOXO3a in NSCLC samples was screened by gene microarray and then verified using Western blot analysis in NSCLC cell lines. Interaction between E2, SIRT1, FOXO3a and PD-L1 was determined. Following ectopic expression and depletion experiments in A549 and H1435 cells, cell proliferation and killing of cytotoxic T lymphocytes (CTLs) on NSCLC cells were evaluated. Xenograft mouse models were prepared to validate the in vivo effect of E2. E2 activated SIRT1 by up-regulating the expression of ERß and thereby weakened the killing of CTLs on NSCLC cells. E2 elevated PD-L1 by up-regulating the ERß/SIRT1 axis to promote the immune escape of NSCLC cells. SIRT1 degraded FOXO3a by reducing the acetylation level of FOXO3a and increased its ubiquitination. E2 inhibited the expression of FOXO3a and elevated PD-L1 expression, thereby promoting the immune escape of NSCLC cells. In vivo results showed that E2 facilitated the growth and metastasis of NSCLC cells in nude mice by elevating ERß via SIRT1/FOXO3a/PD-L1 axis. In summary, our data revealed the critical roles of E2/ERß/SIRT1/FOXO3a/PD-L1 axis in the immune escape of NSCLC cells and suggested that the axis may be promising therapeutic targets for NSCLC.

Advances in the Prediction and Risk Assessment of Lung Cancer-Associated Venous Thromboembolism.

According to the most recent data from the National Cancer Center, venous thromboembolism (VTE) has unsurprisingly become one of the most common complications in lung cancer. VTE not only interferes with the equilibrium of the clotting system but it also affects tumor progression and prognosis. For the identification of high-risk patients, many clinical risk assessment models have been developed and validated based on the risk factors found in previous studies. In this review, we will summarize advances in prediction and risk assessment of VTE, with a focus on early diagnosis and therapy, reduction of mortality, and the burden of medical costs in lung cancer patients.

Upregulated osteoprotegerin expression promotes lung cancer cell invasion by increasing miR-20a expression.

Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor superfamily and a major regulatory factor in osteoclast development. OPG has been previously associated with the malignant behavior of various types of cancer, particularly that of cancer metastasis. However, information on the link between the expression profile of OPG and lung cancer metastasis remained elusive. In the present study, the expression levels of OPG in the serum samples of patients with non-small cell lung cancer (NSCLC) was measured using ELISA. The expression of miRNAs was assessed using reverse transcription-quantitative PCR. A549 or H3122 cell invasion was assessed using Transwell invasion assays. The effect of OPG on the invasiveness of lung cancer cells was evaluated using an experimental mouse lung metastasis model. OPG expression was found to be upregulated in the serum of patients with NSCLC compared with that in healthy individuals. The serum levels of OPG in patients with distant metastasis were observably higher compared with those in patients without metastasis. Functionally, overexpression of OPG in NSCLC cells markedly promoted cell invasion. Mechanistically, increased expression of OPG resulted in upregulation of microRNA (miR)-20a in NSCLC cells. Furthermore, miR-20a promoted NSCLC cell invasion, whilst miR-20a inhibition partially abrogated the effect of OPG on NSCLC cell invasion. Taken together, the present results demonstrated that the OPG/miR-20a axis serve an important role in lung cancer metastasis, which potentially provide an additional novel target for lung cancer treatment.

Integrated analysis reveals lung fibrinogen gamma chain as a biomarker for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable airway disease. This study aimed to identify key genes related to COPD pathogenesis through an integrated transcriptomic and proteomic analysis of lung tissue from COPD subjects undergoing lung resection for malignancy. METHODS: We performed RNA sequencing, gene expression analysis, and gene set enrichment analysis (GSEA) on lung tissue in 13 non-smokers, 16 smokers, and 16 COPD patients. Key genes were verified by RT-qPCR, immunohistochemistry and Western blot in human lung tissues, cigarette smoke extract (CSE)-exposed human bronchial epithelial cell line (BEAS-2B cells), and a cigarette smoke (CS)-induced mouse model. RESULTS: There were 521 differentially expressed genes between non-smokers and smokers, 57 genes between smokers and COPD patients, and 860 genes between non-smokers and COPD patients. Fibrinogen gamma chain (FGG) was highly expressed in COPD patients versus smokers and in COPD patients versus healthy controls. GSEA of the COPD patients with the highest FGG expression were enriched in the B cell receptor signaling pathway, pantothenate and CoA biosynthesis, Fc epsilon RI signaling pathway, and the Toll-like receptor (TLR) signaling pathway. RT-PCR analysis confirmed enhanced FGG mRNA levels in the lungs of both smokers and COPD patients compared to non-smokers and in CSE-exposed cells compared to control cells. FGG protein levels were elevated in the lungs of COPD patients and smokers compared to non-smokers and in the lungs of CS-exposed mice compared to control mice. CONCLUSIONS: FGG may serve as a biomarker for COPD and may play an important role in its pathogenesis.

Sirtuin 7 promotes non­small cell lung cancer progression by facilitating G1/S phase and epithelial­mesenchymal transition and activating AKT and ERK1/2 signaling.

Increasing evidence has indicated the roles of sirtuin 7 (SIRT7) in numerous human cancers. However, the effects and the clinical significance of SIRT7 in human lung cancer is largely unknown. The present research demonstrated that SIRT7 was increased in human lung cancer tumor tissues. SIRT7 upregulation was associated with clinicopathological characteristics of lung cancer malignancy including positive lymph node metastasis, high pathologic stage and large tumor size. SIRT7 was also upregulated in human non­small cell lung cancer (NSCLC) cell lines. Furthermore SIRT7­overexpressed A549 (A549­SIRT7) and SIRT7­knocked down H292 (H292­shSIRT7) human NSCLC cell lines were established. Using these NSCLC cells and xenograft mouse models, it was revealed that SIRT7 overexpression markedly promoted growth and G1 to S cell cycle phase transition as well as migration, invasion and distant lung metastasis in A549 NSCLC cells, whereas SIRT7 knockdown suppressed these processes in H292 NSCLC cells. Mechanistically, in A549 NSCLC cells, SIRT7 overexpression significantly activated not only protein kinase B (AKT) signaling but also extracellular signal­regulated kinase 1/2 (ERK1/2) signaling. SIRT7 overexpression also significantly downregulated cyclin­dependent kinase (CDK) inhibitors including p21 and p27 as well as upregulated cyclins including cyclin D1 and cyclin E1, and CDKs including CDK2 and CDK4. Notably, the epithelial­mesenchymal transition (EMT) process of A549 NSCLC cells was facilitated by SIRT7 overexpression, as evidenced by E­cadherin epithelial marker downregulation and mesenchymal markers (N­cadherin, vimentin, Snail and Slug) upregulation. In addition, SIRT7 knockdown in H292 NSCLC cells exhibited the opposite regulatory effects. Moreover, inhibition of AKT signaling abated the promoting effects of SIRT7 in NSCLC cell proliferation and EMT progression. The present data indicated that SIRT7 accelerated human NSCLC cell growth and metastasis possibly by promotion of G1 to S­phase transition and EMT through modulation of the expression of G1­phase checkpoint molecules and EMT markers as well as activation of AKT and ERK1/2 signaling. SIRT7 could be an innovative potential target for human NSCLC therapy.

Enhanced expression of lncRNA ZXF1 promotes cisplatin resistance in lung cancer cell via MAPK axis.

Long non-coding RNA (lncRNA) ZXF1 has recently been associated with the poor prognosis of lung cancer by promoting metastasis. However, little is known regarding the role of ZXF1 in lung cancer treatment and the underlying mechanism. Here, using lung cancer tissue and chemoresistant lung cancer cells, we investigated the interaction of ZXF1 with the efficacy of cisplatin, the first-line chemotherapy for lung cancer. We found that ZXF1 overexpression in lung cancer tissue increased the risk of treatment failure and tumor recurrence. We also provided evidence that ZXF1 contributed to cisplatin resistance and cancer progression via activating ERK, JNK and p38-mediated MAPK signaling cascade. In contrast, deactivating MAPK pathway by ZXF1 silencing enhanced cisplatin-induced cell cycle arrest and apoptosis by activating p53/p21 axis. Moreover, ZXF1 knockdown suppressed MAPK-regulated expression of MMP-2 and MMP-9, the enzymes responsible for degrading extracellular matrix, and thus decreased the invasion and migration capability of the cells. All these changes inhibited rapid cell proliferation and restored cellular sensitivity to cisplatin treatment. Taken together, our study revealed that lncRNA ZXF1 contributes to cisplatin resistance and leads to the poor prognosis of lung cancer via activating MAPK pathway, which represents as a promising target to optimize lung cancer treatment.

EVI5 is an oncogene that regulates the proliferation and metastasis of NSCLC cells.

BACKGROUND: The Ecotropic viral integration site 5 (EVI5), an important protein in regulating cell cycle, cytokinesis and cellular membrane traffic, functions as a stabilizing factor maintaining anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 in S/G2 phase. However, the mechanism by which EVI5 promotes malignant transformation of non-small cell lung cancer (NSCLC) remains unknown. In the present study, we addressed the role of EVI5 in NSCLC by regulating tumor growth, migration and invasion. METHODS: The expression levels of EVI5 and miR-486-5p in NSCLC tissues and cells were measured by real-time PCR. Meanwhile, EVI5 and its associated protein expression were analyzed by western blot and co-immunoprecipitation assay. Flow cytometry was performed to determine cell proliferation and apoptosis. CCK-8 and clonogenic assays were used to analyze cell viability. Wound healing, transwell migration and matrigel invasion assays were utilized to assess the motility of tumor cells. To investigate the role of EVI5 in vivo, lung carcinoma xenograft mouse model was applied.. RESULTS: EVI5 was upregulated in NSCLC tissues and cell lines when compared with that in normal tissues and cell line. Knockdown of EVI5 in vitro inhibited tumor cell proliferation, migration and invasion in NSCLC cells. Further, inoculation of EVI5-deficient tumor cells into nude mice suppressed tumor proliferation and metastasis compared to control mice inoculated with unmanipulated tumor cells. These data indicated that EVI5 promote the proliferation of NSCLC cells which was consistent with our previous results. Additionally, we showed that EVI5 was directly regulated by miR-486-5p, and miR-486-5p-EVI5 axis affected the NSCLC migration and invasion through TGF-ß/Smad signaling pathway by interacting with TGF-ß receptor II and TGF-ß receptor I. CONCLUSIONS: Based on these results, we demonstrated a new post-transcriptional mechanism of EVI5 regulation via miR-486-5p and the protumoral function of EVI5 in NSCLC by interacting with Emi1 and/or TGF-ß receptors, which provides a new insight into the targeted therapy of NSCLC.

Cigarette smoke-induced lung inflammation in COPD mediated via CCR1/JAK/STAT /NF-κB pathway.

Inflammation is an important cause of chronic obstructive pulmonary disease (COPD) and its acute exacerbation. However, the critical role of C-C chemokine receptor (CCR)1 in progression of cigarette smoke-induced chronic inflammation remains unclear. We studied CCR1 expression using immunohistochemistry, immunofluorescence, and real-time polymerase chain reaction (RT-PCR) in COPD patients and controls. Cytokine levels in peripheral blood were measured by enzyme-linked immunosorbent assay (ELISA). In vitro, we investigated Janus kinase/signal transducers and activators of transcription (JAK/STAT)/nuclear factor-κB (NF-κB) signaling in cigarette smoke extract-induced or CCR1 deficiency/overexpressed mouse macrophage cell line MH-S by RT-PCR and western blot, and measured the cytokine levels in the supernatant with ELISA. We found that CCR1 expression was upregulated in COPD patients and there was a negative correlation between CCR1 mRNA levels and predicted % forced expiratory volume in 1 min. Inflammatory cytokine levels in the peripheral blood were higher in COPD patients than controls, and these were positively correlated with CCR1 levels. CCR1 was shown to play a critical role in regulating smoke-induced inflammation via JAK/STAT3/NF-κB signaling in vitro. CCR1 may play a critical role in airway inflammation in COPD. Additionally, understanding the molecular mechanism may help develop novel methods for the treatment of COPD.

Clinicopathologic Features and the Prognostic Implications of Long Noncoding RNA HOTAIRM1 in Non-Small Cell Lung Cancer.

Aims: The purpose of this study was to explore the value of long noncoding RNA-HOXA transcript antisense RNA myeloid-specific 1 (LncRNA-HOTAIRM1) as a prognostic candidate for detecting non-small cell lung cancer (NSCLC). Materials and Methods: The cancer cell line encyclopedia online database was utilized to analyze HOTAIRM1 expression in different tumor cell lines and to estimate the relationship between HOTAIRM1 and clinicopathologic parameters based on the chi-square test. We compared the LncRNA-HOTAIRM1 levels in cancerous and paracancerous tissues of NSCLC patients using quantitative real-time polymerase chain reaction assays. The Kaplan-Meier method was performed to analyze overall survival (OS). Results: LncRNA-HOTAIRM1 showed varied expression levels in different malignant tumor cell lines. There was a significant association between the expression of HOTAIRM1 and histopathological differentiation, tumor size, tumor/node/metastasis (TNM) stage, and Ki-67 of NSCLC patients. In addition, the relative expression of HOTAIRM1 in NSCLC tissues was significantly higher when compared with the individual patients' matched paracancerous tissues. Patients in the group with low expression levels of HOTAIRM1 had a longer OS than those in the group with high expression levels for lung adenocarcinoma, I-II stages of NSCLC, and NSCLC with smoking history. Conclusion: Our study suggests that LncRNA-HOTAIRM1 is highly expressed in NSCLC, and is associated with a poor prognosis, higher clinicopathologic grade, and smoking. LncRNA-HOTAIRM1 is a potential diagnostic and prognostic biomarker for NSCLCs.

R-spondin family members as novel biomarkers and prognostic factors in lung cancer.

The R-spondin (RSPO) family of secreted proteins consists of four members that have critical roles in embryonic development and organogenesis. However, the expression patterns and the exact roles of the individual RSPO family members in tumorigenesis and progression of lung cancer are unknown, particularly in non-small cell lung cancer, which accounts for 85% of all lung cancer cases. In the present study, data from the ONCOMINE database was used to compare the RNA expression levels of RSPOs in multiple different types of cancer with normal controls. The expression profiles of RSPOs in various types of cancer cell lines were subsequently compared based on data from the Broad Institute Cancer Cell Line Encyclopedia. Using the Kaplan-Meier plotter, the prognostic value of expression of the different RSPOs members was determined for different pathological subtypes of lung cancer. When compared with normal tissues, expression of RSPO1, RSPO2 and RSPO3 was significantly lower in patients with lung cancer. In the survival analysis, increased mRNA expression levels of RSPO1, RSPO2 and RSPO3 were associated with increased survival in patients with lung adenocarcinomas. These results suggest that RSPO1, RSPO2 and RSPO3 may serve as distinct biomarkers and prognostic factors in patients with lung cancer.

Analysis of the long non-coding RNA LINC01614 in non-small cell lung cancer.

The aim of this study was toexplore the long non-coding RNA (lncRNA) expression pattern of non-small cell lung cancer (NSCLC) on a genome-wide scale and investigate their potential biological function in NSCLC.LncRNAs were investigated in 6 pairs of NSCLC and matched adjacent non-tumor lung tissues (NTL) by microarray. A validation cohort was obtained from The Cancer Genome Atlas (TCGA) database and the effect of LINC01614 on diagnosis and prognosis in NSCLC was analyzed. Gene set enrichment analysis (GSEA) was used to predict the potential molecular mechanism of LINC01614, one identified lncRNA.A total of 1392 differentially expressed lncRNAs were identified. LINC01614 was the most aberrantly expressed lncRNA in NSCLC compared with NTL. We confirmed the significantly upregulated LINC01614 in NSCLC patients from TCGA database. Furthermore, in TCGA database, LINC01614 was significantly upregulated in both adenocarcinoma and squamous cell carcinoma. And high expression of LINC01614 indicated poor overall survival of NSCLC patients. A sensitivity of 93% was calculated conditional on a high specificity of 95% for the discrimination of NSCLC tissues from normal tissues. Furthermore, the expression levels of LINC01614 were associated with the stage of tumor, but had no relationship with age and sex. Additionally, GSEA found that LINC01614 might be involved in TGF-ß-, P53-, IGF-IR-mediated, Wnt and RTK/Ras/MAPK signaling pathways.lncRNAs may play key roles in the development of NSCLC. LINC01614 is the most aberrantly expressed lncRNA in NSCLC tissues in our experiment and is also significantly differentially expressed in NSCLC patients from TCGA database. LINC01614 could be a prognostic indicator and has the potential to be a diagnostic biomarker of NSCLC.

MicroRNA-4286 promotes cell proliferation, migration, and invasion via PTEN regulation of the PI3K/Akt pathway in non-small cell lung cancer.

It is well-known that phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor which negatively regulates PI3K/AKT signaling and is activated widely in non-small cell lung cancers (NSCLC). However, genetic alterations in PTEN genes are rare, suggesting an undefined mechanism(s) for their suppression. Notably, growing evidence indicates that PTEN can be regulated by microRNAs involved in cancer progression. In this study, we discover that the miR-4286 is overexpressed in NSCLC and negatively regulates the expression of PTEN. Furthermore, we found that miR-4286 reduces PTEN expression by directly binding to PTEN 3'-untranslated region (UTR), thereby inhibiting NSCLC cell proliferation and mobility. Moreover, mechanistic investigations revealed that miR-4286 overexpression was a result of PTEN-mediated activation of the PI3K/AKT pathway. Taken together, our findings elucidate that miR-4286 promotes the tumorigenesis of NSCLC by interacting with PTEN. This miR-4286-mediated upregulation of PTEN might lead to new therapeutic strategies for NSCLC.