Expression and prognostic value of E2F3 transcription factor in non‑small cell lung cancer

Wu, Lei; Li, Jinfan; Xu, Yiying; Lou, Xiaoli; Sun, Maomin; Wang, Shouli

doi:10.3892/ol.2021.12672

Cited by 13 publications

(14 citation statements)

References 29 publications

(54 reference statements)

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“…Interestingly, there is stronger evidence supporting the STK11-related ICI resistance 11 . In accordance, the cell-cycle promoter E2F3 is a well described tumoral poor prognosis factor, and associated with a low immune signature score when amplified 12 .…”

Section: Discussionmentioning

confidence: 73%

“…The STK11 mutation-induced downregulation of immune checkpoint regulating proteins like PD-L1 and T-cell chemokines favors a ‘‘cold’’ immunosuppressive tumor microenvironment (TME) and contributes to the exclusion of inflamed immune cells such as CD4+ T cells, CD8+ T cells, natural killer cells (NK), and Macrophage type 1 (M1), driving the tumor immune escape 18 . In accordance, the cell-cycle promoter E2F3 is a well described tumoral poor prognosis factor and associated with a low immune signature score when amplified 19(p3) .…”

Section: Discussionmentioning

confidence: 80%

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Interplay between Tumor Mutational Burden and Mutational Profile and its effect on overall survival: A Post Hoc Analysis of Metastatic Patients Treated with Immune Checkpoint Inhibitors

Xavier

Guardia

Lopes

et al. 2022

Preprint

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Importance: Tumor mutational burden (TMB) greater than or equal to 10 mutations per megabase (mut/Mb) has received agnostic FDA approval for pembrolizumab. However, this TMB cut-off alone is not a complete predictor of overall survival (OS) in patients treated with immune checkpoint inhibitors (ICIs). Objective. To analyze the influence of the molecular profile in patients with TMB ≥ 10mut/Mb treated with ICIs. Design, Setting, and Participants. This post-hoc analysis evaluated the clinical and molecular features of tumor-normal pairs from 1,661 patients with solid tumors sequenced using the MSK-IMPACT assay and treated with ICIs. Main Outcomes and Measures. We performed OS analysis and compared the results for TMB thresholds of ≥ 10, ≥ 20, and < 10 mut/Mb. For a TMB ≥ 10mut/Mb, we assessed OS according to mutational status. For all genes exhibiting a correlation with OS (P < 0.05), we conducted a Cox multivariate analysis stratified by median TMB, sex, median age, microsatellite instability (MSI) status, and histology. Results. After a maximum follow-up of 80 months, a total of 1,661 patients were investigated, and survival to ICIs increased with higher TMB cut-offs. The median OS was 42 months for TMB ≥ 10 or 20mut/Mb, and 15 months for TMB < 10 mut/Mb (P < 0.005). Patients harboring a TMB ≥ 10 (N=488, 29%) were further stratified by their somatic mutation profile in key cancer genes. When only genes with n ≥ 5 mutations were considered, mutations in E2F3 or STK11 were correlated with worse OS, and those with mutations in NTRK3, PTPRD, RNF43, TENT5C, TET1 or ZFHX3 were correlated with better OS in TMB-high patients receiving ICIs compared to wild-type patients. These associations were confirmed by univariate and multivariate analyses (P < 0.05). MSI status and clinical features, including age, sex, and histology (except for melanoma), failed to predict outcomes to ICIs in patients with high TMB. Conclusion and relevance. The findings suggest that combining TMB information and mutation profiles in key cancer genes can be used to better qualify patients for ICI treatment and predict their OS.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 80%

Interplay between Tumor Mutational Burden and Mutational Profile and its effect on overall survival: A Post Hoc Analysis of Metastatic Patients Treated with Immune Checkpoint Inhibitors

Xavier

Guardia

Lopes

et al. 2022

Preprint

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“…The mRNA and protein expression levels of E2F3 were both upregulated in NSCLC tumor tissues according to a recent study, and the inhibited expression of E2F3 gene could lead to the decrease of tumor cell metastasis and viability. 22 It has been reported that the expression of E2F4 and E2F5 were significantly increased in lung cancer, but there are few studies on their mechanism in lung cancer progress. In our study, the expression of E2F3, E2F4 and E2F5 were also significantly increased in LUAD, but there was no significant correlation between their expression and the prognosis of LUAD.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the E2F Transcription Factor Family in Human Lung Adenocarcinoma

Wang¹,

Liu²,

Cheang³

et al. 2022

IJGM

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Background E2F transcription factors (E2Fs), code a family of pivotal transcription factors, have been identified as key regulators in tumor tumorigenesis. However, the function of E2F family in human lung adenocarcinoma (LUAD) have not been fully elucidated. Methods Herein, The Cancer Genome Atlas (TCGA) databases, Kaplan-Meier plotter, cBioPortal and TIMER were used to analyze differential expression, prognostic value, genetic alteration and immune cell infiltration of E2Fs in LUAD patients. Results The expression levels of E2Fs ( E2F1-8 ) were all significantly upregulated in LUAD tissues compared with normal lung tissues. All eight E2Fs had low rates of gene mutation in LUAD patients from cBioPortal databases. Survival analysis revealed that E2F2 (P=0.038; HR 1.36; 95% CI 1.02–1.81), E2F7 (P<0.001; HR 1.78; 95% CI 1.33–2.39) and E2F8 (P=0.03; HR 1.37; 95% CI 1.02–1.82) were significantly associated with poor prognosis. Multivariate cox regression analysis found that only E2F7 (P<0.001; HR 2.72; 95% CI 1.75–4.25) was an independent prognostic predictor in LUAD after adjusting common clinical parameters. The receiver operating characteristic (ROC) analysis also found that E2F7 had high diagnostic value for LUAD (AUC=0.901). Further analysis found that E2F7 was significantly associated with LUAD immune cell infiltration of B cell, T cell, neutrophil, and myeloid dendritic cell. E2F7 also have positive correlations with immune checkpoint genes including SIGLEC15, CD274, HAVCR2, PDCD1LG2, CTLA4, TIGIT, LAG3 and PDCD1 in LUAD. Conclusion Our findings showed various association of E2F7 in LUAD diagnostic and prognostic aspects, which suggested its potential in becoming a novel biomarker.

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“…Moreover, the interaction between miR-138-5p and E2F3 was also validated. E2F3 mRNA was highly expressed in lung cancer tissues and associated with poor survival outcomes for the patient, as well as promoted cell proliferation, migration, and invasion [ 16 , 17 , 36 ]. Thus, these data revealed that linc02544 may be involved in regulating LUSC cell proliferative abilities, invasive capacities, and migratory potential through negatively regulating miR-138-5p and regulating E2F3 expression.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of long noncoding RNA linc02544 and its association with overall survival rate and the influence on cell proliferation and migration in lung squamous cell carcinoma

Wei

Zhang

et al. 2022

Discov Onc

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Background Long noncoding RNAs (lncRNAs) exert crucial biological functions by regulating miRNAs, which are implicated in cancer progression and tumorigenesis. A previous study has indicated that lncRNA linc02544 expression is upregulated in lung adenocarcinoma, whereas, the role of linc02544 in LUSC is elusive. Methods The differential linc02544 expression in LUSC tissues and adjacent non-tumor tissues were evaluated with RT-qPCR. Kaplan-Meier curve was conducted to evaluate the clinical prognostic significance of linc02544. Then cellular experiments were performed to assess the influence of linc02544 in LUSC proliferation, invasion, and migration, and a western blot assay was used to measure the metastasis-related protein levels. The downstream miRNAs were verified using the LncBase Experimental v.2 database and dual-luciferase reporter assay. Results Linc02544 was overexpressed in LUSC tissues from positive lymph node metastasis-positive and TNM high-stage patients. Low linc02544 expression was associated with a longer survival rate. Downregulation of linc02544 by si-linc02544 restrained cell growth capacities, migration, and invasion abilities. Expression of MMP-2, MMP-9, and vimentin was decreased while E-cadherin was increased in si-linc02544 cells compared with that in untreated cells. Mechanistically, we identified that linc02544 acted as a sponge of miR-138-5p, which expression had a negative correlation. E2F3 was a potential target of miR-138-5p, Conclusions Notably, high linc02544 expression was associated with severe clinical parameters and was a putative prognostic predictor for patients with LUSC. Downregulation of linc02544 may weaken the LUSC cell proliferation, migration, and invasion by regulating miR-138-5p/E2F3, which maybe serve as a biomarker for the prognosis and target treatment of LUSC.

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Expression and prognostic value of E2F3 transcription factor in non‑small cell lung cancer

Cited by 13 publications

References 29 publications

Interplay between Tumor Mutational Burden and Mutational Profile and its effect on overall survival: A Post Hoc Analysis of Metastatic Patients Treated with Immune Checkpoint Inhibitors

Interplay between Tumor Mutational Burden and Mutational Profile and its effect on overall survival: A Post Hoc Analysis of Metastatic Patients Treated with Immune Checkpoint Inhibitors

Comprehensive Analysis of the E2F Transcription Factor Family in Human Lung Adenocarcinoma

Upregulation of long noncoding RNA linc02544 and its association with overall survival rate and the influence on cell proliferation and migration in lung squamous cell carcinoma

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