Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma.
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ABSTRACT:
SUBMITTER: Han X
PROVIDER: S-EPMC3929783 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Long non-coding RNAs (lncRNAs) have been implicated in pathogenesis of various cancers, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). We used cBioPortal to analyze lncRNA alteration frequencies and their ability to predict overall survival (OS) using 504 LUSC and 522 LUAD samples from The Cancer Genome Atlas (TCGA) database. In LUSC, 624 lncRNAs had alteration rates > 1% and 64 > 10%. In LUAD 625 lncRNAs had alteration rates > 1% and 36 > 10%. Among those, 620 lncRNAs had alteration frequencies > 1% in both LUSC and LUAD, while 22 were LUSC-specific and 23 were LUAD-specific. Twenty lncRNAs had alteration frequencies > 10% in both LUSC and LUAD, while 44 were LUSC-specific and 16 were LUAD specific. Genome ontology and pathway analyses produced similar results for LUSC and LUAD. Two lncRNAs (IGF2BP2-AS1 and DGCR5) correlated with better OS in LUSC, and three (MIR31HG, CDKN2A-AS1 and LINC01600) predicted poor OS in LUAD. Chip-seq and luciferase reporter assays identified potential IGF2BP2-AS1, DGCR5 and LINC01600 promoters and enhancers. This study presented lncRNA landscapes and revealed differentially expressed, highly altered lncRNAs in LUSC and LUAD. LncRNAs that act as oncogenes and lncRNA-regulating transcription factors provide novel targets for anti-lung cancer therapeutics.
| S-EPMC5421846 | biostudies-literature
Project description:Background: Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the two major subtypes of non-small cell lung cancer that pose a serious threat to human health. However, both subtypes currently lack effective indicators for early diagnosis. Methods: To identify tumor-specific indicators and predict cancer-related signaling pathways, LUSC and LUAD gene weighted co-expression networks were constructed. Combined with clinical data, core genes in LUSC and LUAD modules were then screened using protein-protein interaction networks and their functions and pathways were analyzed. Finally, the effect of core genes on survival of LUSC and LUAD patients was evaluated. Results: We identified 12 network modules in LUSC and LUAD, respectively. LUSC modules “purple” and “green” and LUAD modules “brown” and “pink” are significantly associated with overall survival and clinical traits of tumor node metastasis, respectively. Eleven genes from LUSC and eight genes from LUAD were identified as candidate core genes, respectively. Survival analysis showed that high expression of SLIT3, ABI3BP, MYOCD, PGM5, TNXB, and DNAH9 are associated with decreased survival in LUSC patients. Furthermore, high expression of BUB1, BUB1B, TTK, and UBE2C are associated with lower patient survival. Conclusions: We found biomarker genes and biological pathways for LUSC and LUAD. These network hub genes are associated with clinical characteristics and patient outcomes and they may play important roles in LUSC and LUAD.
| S-EPMC9704934 | biostudies-literature
Project description:BackgroundLung cancer is one of the most common malignant tumors in the world. Exportins are closely associated with the cellular activity and disease progression in a variety of different tumors. However, the expression level, genetic variation, immune infiltration, and biological function of different exportins in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), as well as their relationship with the prognosis of patients with LUAD and LUSC have not been fully clarified.MethodsTo analyze the differential expression, prognostic value, genetic variation, biological function, and immune cell infiltration of exportins in patients with LUAD and LUSC, the ONCOMINE; UALCAN; Human Protein Atlas (HPA); Kaplan-Meier plotter; cBioPortal; Search Tool for the Retrieval of Interacting Genes/Proteins (STRING); Database for Annotation, Visualization, and Integrated Discovery (DAVID); Tumor Immune Estimation Resource (TIMER); and LinkedOmics databases were used in this study.ResultsThe transcriptional and protein expression levels of CSE1L and XPO1/5/6/7 were increased in patients with LUAD and LUSC, and the increased transcriptional levels of CSE1L and XPO5/6/7 were related to worse prognosis. An increased transcriptional level of XPO1 was associated with a better prognosis. These results indicated that CSE1L and XPO1/5/6/7 may be potential prognostic biomarkers for the survival of patients with LUAD and LUSC. Moreover, the high mutation rate of exportins in non-small cell lung cancer was 50.48%, and the largest proportion of mutations included high messenger RNA expression. The expression of exportins was significantly correlated with the infiltration of various immune cells. Differentially expressed exportins could regulate the occurrence and development of LUAD and LUSC by involving a variety of microRNAs and transcription factor E2F1.ConclusionsOur study provides novel insights into the selection of prognostic biomarkers of exportins in LUAD and LUSC.
| S-EPMC10183495 | biostudies-literature
Project description:Some reports suggest that Numb is a potential tumor suppressor. However, its role in non-small cell lung cancer remains unclear. Non-small cell lung cancer comprises two major histological subtypes, adenocarcinoma and squamous cell carcinoma. To investigate the role of Numb in tumorigenesis of lung adenocarcinoma and squamous cell carcinoma, we firstly performed loss-of-function and gain-of-function assays. Moreover, Numb expression was investigated in surgically resected lung adenocarcinoma and squamous cell carcinoma tissues by immunohistochemistry and correlations with prognosis were analyzed. Numb suppressed the proliferation, migration, and invasion of adenocarcinoma cells and inhibited Notch signaling and epithelial-mesenchymal transition in vitro. Numb overexpression also inhibited subcutaneous adenocarcinoma tumor growth. In contrast, Numb promoted the proliferation, migration, and invasion of squamous cell carcinoma cells, but did not induce any consistent changes in Notch signaling. High Numb expression was associated with favorable prognosis in patients with lung adenocarcinoma, but not in those with squamous cell carcinoma. Collectively, our data demonstrate that Numb plays distinct roles in lung adenocarcinoma and squamous cell carcinoma. In lung adenocarcinoma, Numb impairs tumor growth and inhibits the Notch pathway and epithelial-mesenchymal transition, whereas in lung squamous cell carcinoma it may promote proliferation.
| S-EPMC6047666 | biostudies-literature
Project description:Our previous study revealed that S100A7 was selectively expressed in lung squamous cell carcinoma tissues but not in adenocarcinoma. Thus far, the functions of S100A7 in lung cancer have remained largely unknown. Here, we reveal that S100A7 overexpression facilitates the transdifferentiation from adenocarcinoma (ADC) to squamous carcinoma (SCC) in several lung cancer cells, which is confirmed by an increase in DNp63 expression and a decrease in thyroid transcription factor 1 (TTF1) and aspartic proteinase napsin (napsin A) expression. Further study finds that activation of the Hippo pathway induces S100A7 expression and further confirms that nuclear YAP acts as a repressor of S100A7 in H292 cells. Subsequently, we verify that TEAD1 is required for YAP transcriptional repression of S100A7. More importantly, we determine that S100A7 overexpression partially rescues lung ADC to SCC transdifferentiation inhibited by YAP overexpression in all tested cells, suggesting that S100A7 and YAP have the opposite effects on lung ADC to SCC conversion. Taken together, our study demonstrates for the first time that S100A7 not only functions as a facilitator of adenous-squamous carcinoma phenotypic transition in lung cancer cells but also that its expression is differentially regulated by the Hippo-YAP pathway.
| S-EPMC5421890 | biostudies-literature
Project description:Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1(+)NGFR(+) fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR(+) cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.
| S-EPMC4112370 | biostudies-literature
Project description:Accumulating evidence indicates that immunotherapy helped to improve the survival and quality-of-life of patients with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) besides chemotherapy and gene targeting treatment. This study aimed to develop immune-related gene signatures in LUAD and LUSC subtypes, respectively. LUAD and LUSC samples were divided into high- and low-abundance groups of immune cell infiltration (Immunity_H and Immunity_L) based on the abundance of immune cell infiltrations. The distribution of immune cells was significantly different between the high- and low-immunity subtypes in LUAD and LUSC samples. The differentially expressed genes (DEGs) between those two groups in LUAD and LUSC contain some key immune-related genes, such as PDL1, PD1, CTLA-4, and HLA families. The DEGs were enriched in multiple immune-related pathways. Furthermore, the seven-immune-related-gene-signature (CD1B, CHRNA6, CLEC12B, CLEC17A, CLNK, INHA, and SLC14A2) prognostic model-based high- and low-risk groups were significantly associated with LUAD overall survival and clinical characteristics. The eight-immune-related-gene-signature (C4BPB, FCAMR, GRAPL, MAP1LC3C, MGC2889, TRIM55, UGT1A1, and VIPR2) prognostic model-based high- and low-risk groups were significantly associated with LUSC overall survival and clinical characteristics. The prognostic models were tested as good ones by receiver operating characteristic, principal component analysis, univariate and multivariate analysis, and nomogram. The verifications of these two immune-related-gene-signature prognostic models showed consistency in the train and test cohorts of LUAD and LUSC. In addition, patients with LUAD in the low-risk group responded better to immunotherapy than those in the high-risk group. This study revealed two reliable immune-related-gene-signature models that were significantly associated with prognosis and tumor microenvironment cell infiltration in LUAD and LUSC, respectively. Evaluation of the integrated characterization of multiple immune-related genes and pathways could help to predict the response to immunotherapy and monitor immunotherapy strategies.
| S-EPMC8649721 | biostudies-literature
Project description:The lung is a complex ecosystem of host cells and microbes often disrupted in pathological conditions. Although bacteria have been hypothesized as agents of carcinogenesis, little is known about microbiota profile of the most prevalent cancer subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC). To characterize lung cancer (LC) microbiota a first a screening was performed through a pooled sequencing approach of 16S ribosomal RNA gene (V3-V6) using a total of 103 bronchoalveaolar lavage fluid samples. Then, identified taxa were used to inspect 1009 cases from The Cancer Genome Atlas and to annotate tumor unmapped RNAseq reads. Microbial diversity was analyzed per cancer subtype, history of cigarette smoking and airflow obstruction, among other clinical data. We show that LC microbiota is enriched in Proteobacteria and more diverse in SCC than ADC, particularly in males and heavier smokers. High frequencies of Proteobacteria were found to discriminate a major cluster, further subdivided into well-defined communities' associated with either ADC or SCC. Here, a SCC subcluster differing from other cases by a worse survival was correlated with several Enterobacteriaceae. Overall, this study provides first evidence for a correlation between lung microbiota and cancer subtype and for its influence on patient life expectancy.
| S-EPMC6731246 | biostudies-literature
Project description:BackgroundImmunohistochemical staining has been widely used in distinguishing lung adenocarcinoma (LUAD) from lung squamous cell carcinoma (LUSC), which is of vital importance for the diagnosis and treatment of lung cancer. Due to the lack of a comprehensive analysis of different lung cancer subtypes, there may still be undiscovered markers with higher diagnostic accuracy.MethodsHerein first, we systematically analyzed high-throughput data obtained from The Cancer Genome Atlas (TCGA) database. Combining differently expressed gene screening and receiver operating characteristic (ROC) curve analysis, we attempted to identify the genes which might be suitable as immunohistochemical markers in distinguishing LUAD from LUSC. Then we detected the expression of six of these genes (MLPH, TMC5, SFTA3, DSG3, DSC3 and CALML3) in lung cancer sections using immunohistochemical staining.ResultsA number of genes were identified as candidate immunohistochemical markers with high sensitivity and specificity in distinguishing LUAD from LUSC. Then the staining results confirmed the potentials of the six genes (MLPH, TMC5, SFTA3, DSG3, DSC3 and CALML3) in distinguishing LUAD from LUSC, and their sensitivity and specificity were not less than many commonly used markers.ConclusionsThe results revealed that the six genes (MLPH, TMC5, SFTA3, DSG3, DSC3 and CALML3) might be suitable markers in distinguishing LUAD from LUSC, and also validated the feasibility of our methods for identification of candidate markers from high-throughput data.
| S-EPMC4561256 | biostudies-literature
Project description:Lung adenocarcinoma (LADC) and squamous cell carcinoma (LSCC) are the most common non-small cell lung cancer histological phenotypes. Accurate diagnosis distinguishing between these two lung cancer types has clinical significance. For this study, we analyzed four Gene Expression Omnibus (GEO) datasets (GSE28571, GSE37745, GSE43580, and GSE50081). We then imported the datasets into the Gene-Cloud of Biotechnology Information online platform to identify genes differentially expressed in LADC and LSCC. We identified DSG3 (desmoglein 3), KRT5 (keratin 5), KRT6A (keratin 6A), KRT6B (keratin 6B), NKX2-1 (NK2 homeobox 1), SFTA2 (surfactant associated 2), SFTA3 (surfactant associated 3), and TMC5 (transmembrane channel-like 5) as potential biomarkers for distinguishing between LADC and LSCC. Receiver operating characteristic curve analysis suggested that KRT5 had the highest diagnostic value for discriminating between these two cancer types. Using the PrognoScan online survival analysis tool and the Kaplan-Meier Plotter, we found that high KRT6A or KRT6B levels, or low NKX2-1, SFTA3, or TMC5 levels correlated with unfavorable prognoses in LADC patients. Further studies will be needed to verify our findings in additional patient samples, and to elucidate the mechanisms of action of these potential biomarkers in non-small cell lung cancer.
| S-EPMC5641087 | biostudies-literature