Transcription factor PAX6 as a novel prognostic factor and putative tumour suppressor in non-small cell lung cancer.
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ABSTRACT:
SUBMITTER: Kiselev Y
PROVIDER: S-EPMC5864921 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:E2F transcription factor 3 (E2F3) plays a vital role in the development of various types of cancer. To verify whether E2F3 is a suitable biomarker for the prognosis of lung cancer, bioinformatics analysis was performed to determine the differential expression level of E2F3 in lung cancer and the surrounding non-tumor tissues, and the results were confirmed in a NSCLC cell line and a tissue microarray (TMA). The relevance of E2F3 in non-small cell lung cancer (NSCLC) was investigated in 19 studies from the Oncomine database and confirmed in The Cancer Genome Atlas database. In the lung cancer cell line A549, the inhibition of E2F3 mRNA expression level led to decreased tumor cell viability and cell migration, which was determined by a Cell Counting Kit-8 and wound healing assays, respectively. Immunohistochemistry analyses of E2F3, Bcl-2, Bax and caspase-3 were performed in the NSCLC TMA (n=50). The assessment of TMA detected the increase of E2F3 protein expression level in the tumor tissues, as compared with that in the non-tumor tissues, which was also correlated with the increase in expression of Bcl-2 in tumors. Analysis of the clinical data from patients with NSCLC revealed that the overexpression of E2F3 was associated with early lymphatic spreading, and poor patient survival time. The OncomiR website was used to predict the E2F3 upstream microRNAs and determine their prognostic value in patients with NSCLC. The results from the present study revealed that E2F3 was overexpressed at both the transcriptional and translational levels in NSCLC tissues, as compared with that in non-tumor tissues. The overexpression of E2F3 was associated with the upregulation of the anti-apoptotic factor, Bcl-2, which may contribute to uncontrolled tumor growth. Thus, E2F3 was shown to have important oncogenic properties in the development of NSCLC, and it may become a potential biomarker for patients with NSCLC.
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Project description:BACKGROUND:Immunotherapy is a promising advance in oncology. Limited information exists regarding the interrelationship between CD47 expression and tumour-associated macrophage-related immuno-microenvironment in patients with non-small cell lung cancer (NSCLC). These factors may predict novel immunotherapy efficacy. PATIENTS AND METHODS:CD47 and PD-L1 expression was retrospectively assessed in 191 resected NSCLC specimens via immunohistochemistry. Forty-six patients with pulmonary infectious diseases were enrolled as the control group. The infiltration of macrophages (M2 and M1) and CD8+ T-lymphocytes was evaluated via dual-immunofluorescence staining. Targeted DNA sequencing was performed on NSCLC specimens. Survival analysis was performed using the Cox model. RESULTS:Using 2+/3+ as?a CD47 positive (CD47pos) expression cut-off, the prevalence of CD47pos expression in NSCLC was 33.0% (63/191), significantly higher than in pulmonary infectious diseases. CD47pos expression was significantly higher in female, non-smoking and adenocarcinoma patients (p=0.020, p<0.001 and p<0.001, respectively). Furthermore, CD47pos expression was significantly correlated with epidermal growth factor receptor mutation (p<0.001). The expression of CD47 (H-score) in NSCLC was negatively correlated with tumour PD-L1 expression (p=0.0346) and tumour mutation burden (p=0.0107). CD47pos expression was independently correlated with poor disease-free survival in patients with resected NSCLC in multivariate Cox regression analysis (p=0.035). CONCLUSION:This study revealed the demographic, molecular and immuno-microenvironment characteristics of CD47 expression in NSCLC. We identified tumour CD47pos expression as an independent prognostic factor for recurrence in resected NSCLC. Our findings illustrate the potential of anti-CD47 treatment in NSCLC.
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Project description:ObjectiveNon-small-cell lung cancer (NSCLC) is one of the most common fatal cancers in the world. Although the treatment of NSCLC has been significantly improved, there is still an unmet need to identify novel targets for developing therapeutic agents and diagnostic/prognostic markers. The aim of this study is explore the role and underlying mechanism of the epithelial splicing regulatory protein (ESRP1) in the development and progression of NSCLC.MethodsA total of 115 participants, 65 cases of NSCLC, 20 cases of precancerous lesions, and 30 cases of benign lung nodules, were included in this study. The expressions of ESRP1 and related transcription factor Twist in enrolled lung tissues were evaluated by histochemistry and immunohistochemistry assay. The survival analysis and related prognosis factors were evaluated by the Kaplan-Meier curve and Cox regression. In addition, the expression of ESRP1 and epithelial-mesenchymal transition (EMT)related transcription factor Twist and EMT markers E-cadherin and N-cadherin were ascertained by immunohistochemical and immunoblotting assay on A549 lung adenocarcinoma cell lines that were exposed to transforming growth factor β1 (TGFβ1).ResultsCompared with normal lung tissues, the abundance of ESRP1 protein was significantly increased in precancerous lesions and lung cancer. Correlation analysis demonstrated that ESRP1 was an independent prognostic factor in NSCLC. The expression of ESRP1 and Twist was positively correlated in lung tissues (r = 0.285, p < 0.001). In vitro analysis further showed that TGFβ1 could upregulate the expression of EMT transcription factor Twist while downregulating ESRP1.ConclusionsOur data suggest that the aberrant expression of ESRP1 is an early event in the development of NSCLC. The ESRP1 could serve as a prognostic biomarker for NSCLC, particularly when combined with Twist. The Twist negatively regulated the expression of ESRP1, emphasizing the role of the TGFβ/ESRP1 pathway in the development of NSCLC, which warrants further investigation.
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Project description:Growing evidence has highlighted the immune response as an important feature of carcinogenesis and therapeutic efficacy in non-small cell lung cancer (NSCLC). This study focused on the characterization of immune infiltration profiling in patients with NSCLC and its correlation with survival outcome. All TCGA samples were divided into three heterogeneous clusters based on immune cell profiles: cluster 1 ('low infiltration' cluster), cluster 2 ('heterogeneous infiltration' cluster) and cluster 3 ('high infiltration' cluster). The immune cells were responsible for a significantly favourable prognosis for the 'high infiltration' community. Cluster 1 had the lowest cytotoxic activity, tumour-infiltrating lymphocytes and interferon-gamma (IFN-?), as well as immune checkpoint molecules expressions. In addition, MHC-I and immune co-stimulator were also found to have lower cluster 1 expressions, indicating a possible immune escape mechanism. A total of 43 differentially expressed genes (DEGs) that overlapped among the groups were determined based on three clusters. Finally, based on a univariate Cox regression model, prognostic immune-related genes were identified and combined to construct a risk score model able to predict overall survival (OS) rates in the validation datasets.
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Project description:BACKGROUND:This study investigated the function of SMAD3 (SMAD family member 3) in regulating PAX6 (paired box 6) in non-small cell lung cancer. METHODS:First, qRT-PCR was employed to detect SMAD3 expression in cancer tissues along with normal tissues and four cell lines, including BEAS-2B, H125, HCC827 and A549 cells. SMAD3 was knocked down by small interference RNA (siRNA), and then its expression was determined via qRT-PCR and Western blot analysis. The correlation between SMAD3 and PAX6 was determined by double luciferase reporter experiments and chromatin immunoprecipitation (ChIP) assay. Cell viability was evaluated by CCK-8 and colony forming assays, while cell migration and invasion were detected by Transwell analysis. RESULTS:SMAD3 and PAX6 were upregulated in lung cancer tissues and cancer cells. Knocking down SMAD3 and PAX6 by transfection with siRNAs specifically suppressed the expression of SMAD3 and PAX6 mRNA and protein levels. SMAD3 could promote PAX6 transcriptional activity by binding to its promoter. Reduced expression of SMAD3 led to the downregulation of PAX6 mRNA and protein levels along with decreased cell migration, invasion, proliferation and viability in A549 and HCC827 cells. PAX6 overexpression altered the si-SMAD3-induced inhibition of cell migration, invasion, proliferation and viability in A549 and HCC827 cells. Additionally, PAX6 knockdown alone also repressed the cell migration, invasion, proliferation and viability of the cell lines. CONCLUSIONS:SMAD3 promotes the progression of non-small cell lung cancer by upregulating PAX6 expression.
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Project description:Background:The Hippo signalling pathway plays an important role in regulating organ size and cell proliferation. Down-regulation of large tumour suppressor (LATS) protein homologs LATS1 or LATS2 has been found in lung cancer. LATS1 and LATS2 are the core components of the Hippo signalling pathway. LATS1 and LATS2 share some conserved structural features and exhibit redundant biological functions. The aim of this study was to dissect the interaction between these two homologs. Methods:In lung adenocarcinoma (AD) cells, protein expression of LATS1 and LATS2 were determined by western blotting; cell viability and apoptosis were measured by MTT and annexin V staining after treatment with cisplatin; subcellular distributions of LATS proteins were determined by immunofluorescence microscopy; LATS2 expression was modulated by shRNA-mediated knockdown or ectopic expression in cancer cell lines. Results:Manipulation of the expression of these two LATS kinases influenced cisplatin response in advanced lung AD cell lines. High LATS2-to-LATS1 ratio in H2023 cells was associated with cisplatin resistance, while low LATS2-to-LATS1 ratio in CL1-0 and CL83 cells was associated with sensitivity to cisplatin. Manipulating the LATS2-to-LATS1 ratio by LATS2 over-expression in CL1-0 and CL83 rendered them resistant to cisplatin treatment, whereas LATS2 knockdown in H2023 alleviated the LATS2-to-LATS1 ratio and sensitized cancer cells to cisplatin exposure. Conclusions:Our data suggested that the ratio of expression of LATS kinases played a role in the modulation of cisplatin sensitivity in advanced lung AD, and targeting of LATS proteins as a novel therapeutic strategy for lung AD deserves further investigation.
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Project description:In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) samples from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.013). Overall, our results demonstrate that ZNF677 is trancriptionally regulated by methylation in NSCLCs, suggest that ZNF677 has tumor cell growth suppressing properties in NSCLCs and that ZNF677 methylation might serve as prognostic parameter in these patients.
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Project description:BackgroundIn multicellular organisms, precise control of cell cycle and the maintenance of genomic stability are crucial to prevent chromosomal alterations. The accurate function of the DNA damage pathway is maintained by DNA repair mechanisms including homologous recombination (HR). Herein, we show that both TFII-I and DBC1 mediate cellular mechanisms of cell-cycle regulation and DNA double strand damage repair.MethodsRegulation of cell cycle by TFII-I and DBC1 was investigated using Trypan blue dye exclusion test, luciferase assay, and flow cytometry analysis. We also analysed the role of TFII-I and DBC1 in DNA double strand damage repair after irradiation by immunofluorescence study, clonogenicity assay, and HR assay.ResultsFlow cytometry analysis revealed a novel function that siRNA-mediated knockdown of endogenous DBC1 resulted in G2/M phase arrest. We also have shown that both endogenous TFII-I and DBC1 activate DNA repair mechanisms after irradiation because irradiation-induced foci formation of TFII-I-γH2AX was observed, and the depletion of endogenous TFII-I or DBC1 resulted in the inhibition of normal HR efficiency.ConclusionThese results reveal novel mechanisms by which TFII-I and DBC1 can modulate cellular fate by affecting cell-cycle control as well as HR pathway.
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Project description:BACKGROUND: Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). METHODOLOGY AND PRINCIPAL FINDINGS: We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). CONCLUSIONS: Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated.
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