Tumor Progression In Lung Cancer Research Articles

Particulate matters 2.5 induce tumor progression in lung cancer by increasing the activity of hnRNPA2B1 resulting in retarding mRNA decay of oxidative phosphorylation.

Particulate matter 2.5 (PM2.5) has been implicated in lung injury and various cancers, yet its precise mechanistic role remains elusive. To elucidate the key signaling pathways underpinning PM2.5-induced lung cancer progression, we embarked on a study examining the impact of PM2.5 both in vitro and in vivo. Lung cancer cell lines, A549 and H157, were employed for the in vitro investigations. Overexpression or knockdown techniques targeting the hnRNPA2B1 protein were implemented. Lung cancer cells were treated with a medium containing PM2.5 and subsequently prepared for in vitro evaluations. Cell growth, invasion, and migration were gauged using transwell and CCK-8 assays. Apoptosis was ascertained through flow cytometry and western blotting of pertinent proteins. Seahorse analyses probed the influence of PM2.5 on lung cancer energy metabolism. The RNA stability assay was employed to discern the impact of PM2.5 on the stability of oxidative phosphorylation-related genes in lung cancer. Our findings revealed that PM2.5 augmented cell proliferation, migration, and invasion rates. Similarly, a diminished apoptosis rate was observed in PM2.5-treated cells. Elevated expression of hnRNPA2B1 was detected in lung cancer cells exposed to PM2.5. Moreover, in cells treated with PM2.5, hnRNPA2B1 knockdown markedly curtailed cell proliferation by inducing G1-S cell cycle arrest and bolstered lung cancer cell apoptosis in vitro; it also curbed xenograft tumor growth. Mechanistically, our data suggest that PM2.5 undermines the stability of mRNA transcripts associated with oxidative phosphorylation (OXPHOS) and augments the formation of processing bodies (P-bodies), leading to an upsurge in OXPHOS levels. In conclusion, PM2.5 appears to drive lung cancer progression and migration by modulating the energy metabolism of lung cancer in a hnRNPA2B1-dependent manner.

Macrophage CD5L is a target for cancer immunotherapy

Reprogramming of immunosuppressive tumor-associated macrophages (TAMs) presents an attractive therapeutic strategy in cancer. The aim of this study was to explore the role of macrophage CD5L protein in TAM activity and assess its potential as a therapeutic target. Monoclonal antibodies (mAbs) against recombinant CD5L were raised by subcutaneous immunization of BALB/c mice. Peripheral blood monocytes were isolated from healthy donors and stimulated with IFN/LPS, IL4, IL10, and conditioned medium (CM) from different cancer cell lines in the presence of anti-CD5L mAb or controls. Subsequently, phenotypic markers, including CD5L, were quantified by flow cytometry, IF and RT-qPCR. Macrophage CD5L protein expression was studied in 55 human papillary lung adenocarcinoma (PAC) samples by IHC and IF. Anti-CD5L mAb and isotype control were administered intraperitoneally into a syngeneic Lewis Lung Carcinoma mouse model and tumor growth was measured. Tumor microenvironment (TME) changes were determined by flow cytometry, IHC, IF, Luminex, RNAseq and RT-qPCR. Cancer cell lines CM induced an immunosuppressive phenotype (increase in CD163, CD206, MERTK, VEGF and CD5L) in cultured macrophages. Accordingly, high TAM expression of CD5L in PAC was associated with poor patient outcome (Log-rank (Mantel-Cox) test p=0.02). We raised a new anti-CD5L mAb that blocked the immunosuppressive phenotype of macrophages invitro. Its administration invivo inhibited tumor progression of lung cancer by altering the intratumoral myeloid cell population profile and CD4+ T-cell exhaustion phenotype, thereby significantly modifying the TME and increasing the inflammatory milieu. CD5L protein plays a key function in modulating the activity of macrophages and their interactions within the TME, which supports its role as a therapeutic target in cancer immunotherapy. For a full list of funding bodies, please see the Acknowledgements.

Mechanism of lnRNA-ICL involved in lung cancer development in COPD patients through modulating microRNA-19-3p/NKRF/NF-κB axis

The incidence of lung cancer (LC) in chronic obstructive pulmonary disease (COPD) patients is dozens of times higher than that in patients without COPD. Elevated activity of nuclear factor-k-gene binding (NF-κB) was found in lung tissue of patients with COPD, and the continuous activation of NF-κB is observed in both malignant transformation and tumor progression of LC, suggesting that NF-κB and its regulators may play a key role in the progression of LC in COPD patients. Here, we report for the first time that a key long non-coding RNA (lncRNA)-ICL involved in the regulation of NF-κB activity in LC tissues of COPD patients. The analyses showed that the expression of ICL significantly decreased in LC tissues of LC patients with COPD than that in LC tissues of LC patients without COPD. Functional experiments in vitro showed that exogenous ICL only significantly inhibited the proliferation, invasion and migration in primary tumor cells of LC patients with COPD compared to LC patients without COPD. Mechanism studies have shown that ICL could suppress the activation of NF-κB by blocking the hsa-miR19-3p/NKRF/NF-κB pathway as a microRNA sponge. Furthermore, In vivo experiments showed that exogenous ICL effectively inhibited the growth of patient-derived subcutaneous tumor xenografts (PDX) of LC patients with COPD and significantly prolonged the survival time of tumor-bearing mice. In a word, our study shows that the decrease of ICL is associated with an increased risk of LC in patients with COPD, ICL is not only expected to be a new therapeutic target for LC in COPD patients, but also has great potential to be used as a new marker for evaluating the occurrence, severity stratification and prognosis of LC in patients with COPD.

PM2.5 promotes lung cancer progression through activation of the AhR‐TMPRSS2‐IL18 pathway

Particulate matter 2.5 (PM2.5) is a risk factor for lung cancer. In this study, we investigated the molecular mechanisms of PM2.5 exposure on lung cancer progression. We found that short‐term exposure to PM2.5 for 24 h activated the EGFR pathway in lung cancer cells (EGFR wild‐type and mutant), while long‐term exposure of lung cancer cells to PM2.5 for 90 days persistently promoted EGFR activation, cell proliferation, anchorage‐independent growth, and tumor growth in a xenograft mouse model in EGFR‐driven H1975 cancer cells. We showed that PM2.5 activated AhR to translocate into the nucleus and promoted EGFR activation. AhR further interacted with the promoter of TMPRSS2, thereby upregulating TMPRSS2 and IL18 expression to promote cancer progression. Depletion of TMPRSS2 in lung cancer cells suppressed anchorage‐independent growth and xenograft tumor growth in mice. The expression levels of TMPRSS2 were found to correlate with nuclear AhR expression and with cancer stage in lung cancer patient tissue. Long‐term exposure to PM2.5 could promote tumor progression in lung cancer through activation of EGFR and AhR to enhance the TMPRSS2‐IL18 pathway.

Methylation patterns of Lys9 and Lys27 on histone H3 correlate with patient outcome and tumor progression in lung cancer

BackgroundsHistone methylation is recognized as an important component of the epigenetic mechanisms of cancer initiation and progression. Previous studies have demonstrated that aberrant alterations in histone methylation are associated with lung cancer. However, novel and specific epigenetic biomarkers for monitoring lung adenocarcinoma remain unknown. MethodsA retrospective clinicopathological analysis was performed on 71 lung adenocarcinoma (LUAD) patients who received complete ablative surgical treatment. Tissue arrays were made from the paraffin-embedded LUAD tumor tissues, and these, together with corresponding normal tissues, were examined through immunohistochemistry for several markers: histone 3 lysine 9 di-methylation (H3K9me2), histone 3 lysine 9 tri-methylation (H3K9me3), and histone 3 lysine 27 tri-methylation (H3K27me3). The expression level of each marker was analyzed according to the histological classification and clinical prognosis data. ResultsCompared with peri-cancerous tissues, cancerous tissues distinctly expressed higher proportions of H3K9me2, H3K9me3, and H3K27me3. A higher expression pattern of H3K27me3 was associated with the poorly differentiation and unfavorable prognosis in LUAD. Based on histological types, it was found that the H3K27me3 level of patients with micropapillary type is high, and it is related to worse prognosis. ConclusionsThe findings of this study show that the H3K27me3 and micropapillary type are malignant clinical factors of LUAD. H3K27me3 reduction is a novel epigenetic biomarker for defining high-risk LUAD and predicting worse prognosis. Immunohistochemical evaluation of H3K27me3 expression is an economic, easily available, and readily adaptable method.

Clinical relevance and therapeutic potential of IL-38 in immune and non-immune-related disorders

Interleukin-38 (IL-38) is the most recent member of the IL-1 family that acts as a natural inflammatory inhibitor by binding to cognate receptors, particularly the IL-36 receptor. In vitro, animal and human studies on autoimmune, metabolic, cardiovascular and allergic diseases, as well sepsis and respiratory viral infections, have shown that IL-38 exerts an anti-inflammatory activity by modulating the generation and function of inflammatory cytokines (e.g. IL-6, IL-8, IL-17 and IL-36) and regulating dendritic cells, M2 macrophages and regulatory T cells (Tregs). Accordingly, IL-38 may possess therapeutic potential for these types of diseases. IL-38 down-regulates CCR3+ eosinophil cells, CRTH2+ Th2 cells, Th17 cells, and innate lymphoid type 2 cells (ILC2), but up-regulates Tregs, and this has influenced the design of immunotherapeutic strategies based on regulatory cells/cytokines for allergic asthma in future studies. In auto-inflammatory diseases, IL-38 alleviates skin inflammation by regulating γδ T cells and limiting the production of IL-17. Due to its ability to suppress IL-1β, IL-6 and IL-36, this cytokine could reduce COVID-19 severity, and might be employed as a therapeutic tool. IL-38 may also influence host immunity and/or the components of the cancer microenvironment, and has been shown to improve the outcome of colorectal cancer, and may participate in tumour progression in lung cancer possibly by modulating CD8 tumour infiltrating T cells and PD-L1 expression. In this review, we first briefly present the biological and immunological functions of IL-38, and then discuss the important roles of IL-38 in various types of diseases, and finally highlight its use in therapeutic strategies.

Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an important regulator of extracellular matrix turnover that has been traditionally regarded as a potential tumor suppressor owing to its inhibitory effects of matrix metalloproteinases. Intriguingly, this interpretation has been challenged by the consistent observation that increased expression of TIMP-1 is associated with poor prognosis in virtually all cancer types including lung cancer, supporting a tumor-promoting function. However, how TIMP-1 is dysregulated within the tumor microenvironment and how it drives tumor progression in lung cancer is poorly understood. We analyzed the expression of TIMP-1 and its cell surface receptor CD63 in two major lung cancer subtypes: lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), and defined the tumor-promoting effects of their interaction. We found that TIMP-1 is aberrantly overexpressed in tumor-associated fibroblasts (TAFs) in ADC compared to SCC. Mechanistically, TIMP-1 overexpression was mediated by the selective hyperactivity of the pro-fibrotic TGF-β1/SMAD3 pathway in ADC-TAFs. Likewise, CD63 was upregulated in ADC compared to SCC cells. Genetic analyses revealed that TIMP-1 secreted by TGF-β1-activated ADC-TAFs is both necessary and sufficient to enhance growth and invasion of ADC cancer cells in culture, and that tumor cell expression of CD63 was required for these effects. Consistently, in vivo analyses revealed that ADC cells co-injected with fibroblasts with reduced SMAD3 or TIMP-1 expression into immunocompromised mice attenuated tumor aggressiveness compared to tumors bearing parental fibroblasts. We also found that high TIMP1 and CD63 mRNA levels combined define a stronger prognostic biomarker than TIMP1 alone. Our results identify an excessive stromal TIMP-1 within the tumor microenvironment selectively in lung ADC, and implicate it in a novel tumor-promoting TAF-carcinoma crosstalk, thereby pointing to TIMP-1/CD63 interaction as a novel therapeutic target in lung cancer.

Deletion of TRIB3 disrupts the tumor progression induced by integrin \u03b1v\u03b23 in lung cancer

BackgroundIntegrin αvβ3 has been proposed as crucial determinant for tumor sustained progression and a molecular marker for the estimation of tumor angiogenesis. Our study suggested that integrin αvβ3 could efficiently promote lung cancer cell proliferation and stem-like phenotypes in a tribbles homolog 3 (TRIB3) dependent manner.ResultIntegrin αvβ3 could mediate the activation of FAK/AKT pro-survival signaling pathway. Meanwhile, activated TRIB3 interacted with AKT to upregulated FOXO1 and SOX2 expression, resulting in sustained tumor progression in lung cancer. Our further analysis revealed that TRIB3 was significantly upregulated in lung tumor tissues and correlated with the poor outcome in clinical patients, indicating the potential role of TRIB3 in diagnostic and prognostic estimation for patients with lung cancer.ConclusionOur study showed here for the first time that integrin αvβ3 promote lung cancer development by activating the FAK/AKT/SOX2 axis in a TRIB3 dependent signaling pathway, and interrupting TRIB3/AKT interaction significantly improved the outcome of chemotherapy in tumor-bearing mice, representing a promising therapeutic strategy in lung cancer.

Untargeted metabolomics profiling in a mouse model of lung cancer treated with thermal ablation

ABSTRACT Thermal ablation is widely used in the treatment of lung cancer and is beneficial for the overall survival of patients in clinic. However, there is barely a priority in which ablation system should be chosen under different periods of tumor progression in lung cancer. The present study investigated different modes of thermal ablation systems in mice with transplanted Lewis lung carcinoma tumors and their various biological effects in local regions using untargeted metabolomics. The results showed that thermal ablation could significantly suppress tumor growth and the differentially expressed metabolites of tumors after ablation relative to untreated tumors concentrated on organic compounds, organic acids and derivatives, nucleosides, nucleotides, and lipids. The upregulated metabolites indicated an inflammatory reaction in the ablation groups at an early stage after ablation. Steroid hormone and tryptophan metabolism, which are associated with immune responses, were modulated after both cryoablation and hyperthermal ablation. Characteristically, the results also indicated that cryoablation suppressed glucose oxidation and carbohydrate metabolism of tumor, while hyperthermal ablation suppressed lipid metabolism of tumor. In conclusion, thermal ablation could inhibit tumor growth under either freezing or heating modes with characteristic different biological effects on tumors.

RMI2 is a prognostic biomarker and promotes tumor growth in hepatocellular carcinoma.

Genomic instability is a hallmark of all cancers. RMI2 is a crucial component of the BLM-TopoIIIa-RMI1-RMI2 complex that maintains genome stability. It has been shown to accelerate tumor progression in lung cancer, cervical cancer, and prostate cancer. However, its expression and function in hepatocellular carcinoma (HCC) remain poorly defined. In this study, gene expression data and corresponding clinical information of HCC were downloaded from the TCGA, ICGC, and GEO databases. The expression level and clinical significance of RMI2 in HCC were then analyzed. In addition, cellular and molecular biology experiments were conducted to explore the effects of silencing and overexpression of RMI2 on human liver cancer cells and the associated mechanisms. The results showed that RMI2 expression was elevated in HCC tissues. High expression of RMI2 was correlated with shorter survival and poor prognosis of patients. The results of CCK-8, Edu, and clonogenic assays confirmed that RMI2 overexpression promoted the proliferation of HCC cells. Flow cytometric analysis demonstrated that RMI2 overexpression enhanced G1-S phase transition and decreased apoptosis. Moreover, the protein expression of key effector molecules in the p53 signaling pathway was reduced following RMI2 overexpression. In summary, these results indicate that RMI2 promotes the growth of HCC cells and suppresses their apoptosis by inhibiting the p53 signaling pathway. This study provides new insights into the mechanisms driving HCC tumorigenesis and new therapeutic targets.

P62.07 Investigation of Metabolic Vulnerabilities Specific to STK11-mutant Lung Cancer

Tumor suppressor Serine/Threonine Kinase 11 (STK11) is inactivated in 25-30% of patients with lung adenocarcinoma. Functionally, it is the predominant upstream kinase of adenosine monophosphate-activated protein kinase (AMPK), a key regulator in cell metabolism maintaining energy homeostasis. However, no clinical targeted therapies are available for STK11-mutant lung cancer. An altered metabolism is a characteristic of cancer and differs in cancer types, histological subtypes or genetic backgrounds. Therefore, identifying metabolic vulnerabilities specific to a certain cancer subtype/genetic mutation is essential in terms of precision oncology. Mitochondrial Solute Carriers (SLC) transport various metabolites through the inner membrane of the mitochondria, thereby supporting rapid growth of cancer cells, which plays a critical role in tumor initiation and progression. In lung cancer, it remains to be defined whether the STK11 mutation confers a specific metabolic vulnerability. Candidate genes (N = 53) in the SLC family were then investigated. We integrated the transcriptomic and whole-exome sequencing data from the TCGA (The Cancer Genome Atlas) lung adenocarcinoma cohort (N = 507). Genetically mutually exclusive and co-occurring analysis was performed with open-source bioinformatic tools R (https://www.r-project.org). Integrated analyses reveal that, in the SLC family, SLC25A10 is the most strikingly overexpressed gene in clinical samples of patients with lung adenocarcinoma compared to the matched normal lung tissue. More importantly, compared to the corresponding wild-type lung adenocarcinoma tumor samples, upregulated SLC25A10 is exclusively associated with STK11 mutations while not with other frequently-altered genes (> 5% in lung cancer; TP53, RB1, NF1, EGFR, KRAS, MET, ALK). This exclusivity suggests that SLC25A10 is a potential target in lung cancer harbouring STK11 mutations. Further, analysis of the genetic changes (gene mutations or copy number) of SLC25A10 and STK11 with regard to their exclusion and co-occurrence status revealed a significant, mutually exclusive pattern (adjust p-value < 0.0001), indicating functional redundancy between the two genes in the pathogenesis of lung adenocarcinoma. In the present in silico analysis, we identified that SLC25A10 might play a critical role in tumor progression of lung cancer with STK11 mutations. Therefore, we concluded that the altered metabolic pathways in lung cancer harbouring STK11 mutations might be a potential therapeutic target in this cancer type.

Circular RNA Signature in Lung Adenocarcinoma: A MiOncoCirc Database-Based Study and Literature Review.

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) with a structure of covalently closed continuous loops, which can regulate gene expression by acting as a microRNA sponge or through other mechanisms. Recent studies have identified that the expression of candidate circRNAs are dysregulated in various tumors and hence are considered as promising diagnostic or therapeutic targets across cancer types. However, the expression and function of circRNAs in lung adenocarcinoma (LUAD) remains unclear. In this article, we investigated the expression of circRNAs in LUAD via MiOncoCirc, which is the first and comprehensive database characterizing circRNAs across >2,000 cancer samples using an exome capture RNA sequencing. We identified seven abnormally expressed circRNAs in LUAD, including circCDR1-AS, circHIPK3, circFNDC3B, circPCMTD1, circRHOBTB3, circFAM13B, and circMAN1A2, as well as conducted a literature review about the function and features of these circRNAs. Previous studies have demonstrated that circCDR1-AS, circMAN1A2, and circHIPK3 were upregulated and significantly correlated with a poor survival, or promoted the tumor progression in lung cancer, whereas other circRNAs have not been fully explored. Besides, we reviewed all the publications regarding circRNAs and LUAD, and noticed that the dysregulation of these circRNAs impacts the development of LUAD through a variety of regulatory mechanisms. In conclusion, the underlying mechanisms of aberrant expression and functions of circRNAs in LUAD are worthy of being further investigated.

PRDX2 Promotes the Proliferation and Metastasis of Non-Small Cell Lung CancerIn VitroandIn Vivo

Purpose Previous studies have reported that the levels of PRDX2 were correlated with tumorigenicity, recurrence, and prognosis of patients with different cancers. We investigated the association between PRDX2 levels and the prognosis of lung cancer patients. We also measured PRDX2 expression of non-small cell lung cancer (NSCLC) cells and examined its roles in the proliferation and migration in vitro and in vivo. Methods We used the Kaplan–Meier plotter to analyze the survival of different levels of PRDX2 in lung cancer patients. The expression of PRDX2 in normal bronchial epithelial cell line and NSCLC cell lines was measured by qRT-PCR and western blot assays. Biological functions of NSCLC cells were detected by CCK8 and Transwell assays. We constructed tumor growth model using subcutaneously injection of nude mice and metastasis model by tail vein injection in vivo. The protein levels of proliferation related markers were measured by immunohistochemistry assay. Immunofluorescence method was used to detected EMT-related proteins. Results The high levels of PRDX2 were associated with bad prognosis in lung cancer patients, especially in patients with adenocarcinoma. The expression of PRDX2 in NSCLC cell lines was higher than normal bronchial epithelial cells. Knockdown of PRDX2 inhibited the proliferation, migration, and invasion in A549 cells, while overexpression of PRDX2 promoted the malignancy in NCI-H1299 cells in vitro. Silencing PRDX2 restrained tumor growth and repressed lung metastasis by EMT in vivo. Conclusion Our data indicates that PRDX2 functions as a protumor regulator and is involved in tumorigenesis and tumor progression of lung cancer.

Identification and validation of HELLS (Helicase, Lymphoid-Specific) and ICAM1 (Intercellular adhesion molecule 1) as potential diagnostic biomarkers of lung cancer.

Although lung cancer is one of the greatest threats to human health, its signaling pathway and related genes are still unknown. This study integrates data from three groups of people to study potential key candidate genes and pathways related to lung cancer. Expression profiles (GSE18842, GSE19188 and GSE27262), including 162 tumor tissue and 135 adjacent normal lung tissue samples, were integrated and analyzed. Differentially expressed genes (DEGs) and candidate genes were identified, their expression pathways were analyzed, and the diethylene glycol-related protein–protein interaction (PPI) network was analyzed. We identified 232 shared DEGs (40 upregulated and 192 down-regulated) from the three GSE datasets. The DEGs were clustered according to function and signaling pathway for significant enrichment analysis. In total, 129 nodes/DEGs were identified from the DEG PPI network complex. An improved prognosis was associated with increased Helicase, Lymphoid-Specific (HELLS) and decreased Intercellular adhesion molecule 1 (ICAM1) mRNA expression in lung cancer patients. In conclusion, we used integrated bioinformatics analysis to identify candidate genes and pathways in lung cancer to show that HELLS and ICAM1 might be the key genes related to tumorigenesis or tumor progression in lung cancer. Additional studies are needed to further explore the involved functional mechanisms.

Liquid biopsy as indication of tumour progression in lung cancer: a potential intervention in tertiary prevention

In the era of personalised therapies, liquid biopsy is considered an important diagnostic tool in the clinical management of cancer patients. Tissue specimen represents the gold standard for molecular evaluation of specific gene targets alterations that lead cancer patients to benefit of a "tailed therapy" based on molecular features of the tumour. This innovative source of nucleic acids was introduced in clinical setting only for non-small-cell lung cancer (NSCLC) patients to test epidermal grow factor receptor (EGFR) mutations when tissue is not available for a number of reasons (difficult access to the lesion, the presence of other disabling pathologies, especially in elderly patients, rejection by the patient, etcetera) or to monitor acquired resistance mutation after a first line of treatment. The present study aimed at assessing the diagnostic potential of liquid biopsy in balanced tertiary screening modelling. The cases relating to 5 years of activity regarding to molecular diagnostics performed on liquid biopsy specimens in the Predictive diagnostic laboratory of the University hospital "Federico II" of Naples (Campania Region, Southern Italy) were reviewed. Laboratory data were collected through the software SPSS. Non-parametric analysis was performed in order to test the differences between "wild type" patients or not. A multivariate logistic model was performed in order to assess the effect of mutation, age, and gender on the tumour progression. The results of the revision concern 515 total cases (almost of all plasma or peripheral blood), which allowed to evaluate the liquid biopsies for women and men. The average age of the patients is 66.3 years, and the 25° percentile is 59 years. The cases are: 221 basal and 294 by progression. The cases with mutation, as expected, have an odds ratio of 4,15, compared to the basal, to have a tumour progression (95%IC 2,7-6,3), regardless of gender and age. The detected mutations were 131 from different types of pulmonary carcinomas. Working on case data, specifying the characteristics of the patients with mutations will drive a further estimate in tertiary prevention screening designs.

Netrin‑1 interference potentiates epithelial‑to‑mesenchymal transition through the PI3K/AKT pathway under the hypoxic microenvironment conditions of non‑small cell lung cancer.

Netrin‑1 is overexpressed in several types of cancer. However, whether netrin‑1 can potentiate hypoxia‑induced tumor progression in lung cancer has not been reported to date. Thus, the objective of the present study was to investigate whether netrin‑1 regulates cancer cell migration and invasion under hypoxic conditions in lung cancer and explore the underlying mechanism. A three‑dimensional microfluidic chip was used to observe real‑time changes in cancer cells, and cobalt chloride (CoCl2) was used to simulate a hypoxic microenvironment. Netrin‑1 siRNA was employed in the A549 and PC9 cell lines to downregulate the expression of netrin‑1. Microfluidic chip, wound healing and Transwell assays were used to examine cell migration and invasion. The expression levels of E‑cadherin and vimentin were detected by western blotting. The data demonstrated that netrin‑1 mediated epithelial‑to‑mesenchymal transition (EMT) of A549 and PC9 cells invitro, which may be associated with the phosphoinositide3 kinase/AKT pathway. This effect of netrin‑1 on the EMT was not observed in the normoxic microenvironment. In this retrospective study, netrin‑1 concentrations were evaluated in serum obtained from patients with non‑small cell lung cancer (NSCLC) and compared with healthy control samples by quantitative enzyme‑linked immunosorbent analysis. The serum concentration of netrin‑1 was found to be significantly higher in NSCLC patients compared with that in healthy donors. Taken together, the findings of the present study highlight a novel role for netrin‑1 in tumor development under hypoxia in NSCLC and provide further evidence for the use of netrin‑1 as a therapeutic target.

LEF1-AS1 contributes to proliferation and invasion through regulating miR-544a/ FOXP1 axis in lung cancer

SummaryLong non-coding RNAs (lncRNAs) are increasingly recognized as important regulators in tumor development. This study aims to investigate the potential role oflncRNALEF1-AS1, in the progression of lung cancer. Quantitative real-time PCR (qRT-PCR) and western blot assays showed that LEF1-AS1 was upregulated while miR-544a was downregulated in lung cancer specimens and cells. Overexpression of LEF1-AS1 led to the enhancement of cell proliferation and invasion, revealed by CCK-8 assay and transwell assay. A negative correlation was found between LEF1-AS1 and miR-544a. BLAST analysis and dual-luciferase assay confirmed that FOXP1 is a downstream effector of miR-544a. Therefore, the LEF1-AS1/miR-544a/FOXP1 axis is an important contributor to lung cancer progression. Collectively, our novel data uncovers a new mechanism that governs tumor progression in lung cancer and provides new targets that may be used for disease monitoring and therapeutic intervention of lung cancer.

Down-regulation of microRNA-200b is a potential prognostic marker of lung cancer in southern-central Chinese population.

MicroRNAs (miRNAs) may regulate diverse biological processes and play an important role in cancer. And MiRNAs have been proposed as a useful tool for lung cancer diagnosis and therapeutics in cancer. The purpose of the present study was to investigate the association among the expression level of mature miR-200b-5p in peripheral blood and the risk of lung cancer and clinic pathological characteristics. This case-control study included 24 patients with lung cancer and 12 healthy controls. MiR-200b expression was deleted using real-time PCR. and the miR-200b expression of normal controls was significantly higher than that in lung cancer patients (1732.13 pg/mL vs 881.67 pg/mL, P < 0.05), no difference with age, sex, tissue type and clinical stage of lung cancer patients (P > 0.05). Furthermore, miR-200b expression level fluctuated with tumor progression in lung cancer, and there was highly significant for clinical stage II compared with the clinical stage III (P < 0.05). In addition, the down-regulation of miR-200b showed a highly discriminative receiver operating characteristic (ROC) curve profile, clearly distinguishing cancer patients from cancer-free subjects with an area under the ROC curve (AUROC) of 0.87. The detection of miR-200b expression yielded 83.30% sensitivity and 100.00% specificity in the diagnosis of lung cancer. Therefore, these findings suggested that miR-200b may be used as a marker for the detection and diagnosis of lung cancer in peripheral blood.

Periostin is a negative prognostic factor and promotes cancer cell proliferation in non-small cell lung cancer.

Periostin is a matricellular protein that is secreted by fibroblasts and interacts with various cell-surface integrin molecules. Although periostin is known to support tumor development in human malignancies, little is known about its effect on lung-cancer progression. We here demonstrate that periostin is a negative prognostic factor that increases tumor proliferation through ERK signaling in non-small cell lung carcinoma. We classified 189 clinical specimens from patients with non-small cell lung-cancer according to high or low periostin expression, and found a better prognosis for patients with low rather than high periostin, even in cases of advanced-stage cancer. In a syngenic implantation model, murine Ex3LL lung-cancer cells formed smaller tumor nodules in periostin−/− mice than in periostin+/+ mice, both at the primary site and at metastatic lung sites. An in vitro proliferation assay showed that stimulation with recombinant periostin increased Ex3LL-cell proliferation. We also found that periostin promotes ERK phosphorylation, but not Akt or FAK activation. These findings suggest that periostin represents a potential target in lung-cancer tumor progression.

Overexpression of MCPH1 inhibits the migration and invasion of lung cancer cells.

BackgroundThe role of dysfunction of MCPH1, a recently identified tumor suppressor gene, has not yet been established in lung cancer. In our previous study, it was reported that MCPH1 expression is downregulated in lung cancer tissues and that MCPH1 overexpression inhibits the proliferation of non-small-cell lung cancer cells. The results can be found in the APJC and Oncology Letters journals.MethodsKaplan-Meier survival analysis was conducted to explore the prognostic significance of MCPH1. Cell experiments were performed to investigate the effects of MCPH1 on the biologic behaviors of lung cancer cells.ResultsIn the current study, microarray analysis of MCPH1 revealed that lung cancer patients with high MCPH1 expression had longer relapse-free survival. Overexpression of MCPH1 in A549 lung carcinoma cells successfully inhibited cell migration and invasion. Moreover, overexpression of MCPH1 inhibited migration and invasion by regulating the activities of several proteins that control the epithelial–mesenchymal transition, such as Slug, Snail, E-cadherin, Mdm2, and p53.ConclusionOur results indicate that downregulation of MCPH1 correlates with tumor progression in lung cancer, and hence MCPH1 may be an important tumor suppressor gene and a novel candidate therapeutic target in lung cancer.