PNO1, a Novel Protein Regulated by miR-340-5p, Serves As a Potential Biomarker and Promotes Lung Adenocarcinoma Progression

AbstractPulmonary surfactant protein A1 (SFTPA1) is a member of the C-type lectin subfamily that plays a critical role in maintaining lung tissue homeostasis and the innate immune response. SFTPA1 disruption can cause several acute or chronic lung diseases, including lung cancer. However, little research has been performed to associate SFTPA1 with immune cell infiltration and the response to immunotherapy in lung cancer. The findings of our study describe the SFTPA1 expression profile in multiple databases and was validated in BALB/c mice, human tumor tissues, and paired normal tissues using an immunohistochemistry assay. High SFTPA1 mRNA expression was associated with a favorable prognosis through a survival analysis in lung adenocarcinoma (LUAD) samples from TCGA. Further GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that SFTPA1 was involved in the toll-like receptor signaling pathway. An immune infiltration analysis clarified that high SFTPA1 expression was associated with an increased number of M1 macrophages, CD8+ T cells, memory activated CD4+ T cells, regulatory T cells, as well as a reduced number of M2 macrophages. Our clinical data suggest that SFTPA1 may serve as a biomarker for predicting a favorable response to immunotherapy for patients with LUAD. Collectively, our study extends the expression profile and potential regulatory pathways of SFTPA1 and may provide a potential biomarker for establishing novel preventive and therapeutic strategies for lung adenocarcinoma.

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LINC00942 Promotes Tumor Proliferation and Metastasis in Lung Adenocarcinoma via FZD1 Upregulation

Technology in Cancer Research & Treatment ◽

10.1177/1533033820977526 ◽

2021 ◽

Vol 20 ◽

pp. 153303382097752

Author(s):

Ronghua Wang ◽

Xiuyun Wang ◽

Jingtao Zhang ◽

Yanpei Liu

Keyword(s):

Lung Adenocarcinoma ◽

Wnt Signaling ◽

Molecular Mechanisms ◽

Bioinformatic Analysis ◽

Luciferase Reporter ◽

Regulatory Relationship ◽

Potential Biomarker ◽

Proliferation And Metastasis ◽

Tumor Proliferation And Metastasis ◽

Dual Luciferase Reporter Assay

Background: Long non-coding RNAs (lncRNAs) have been reported to play important roles in the progression of human cancers. Herein, bioinformatic analysis identified that LINC00942 was a highly overexpressed lncRNA in lung adenocarcinoma (LUAD). The present study aimed to explore the roles and possible molecular mechanisms of LINC00942 in LUAD. Methods: First, on the basis of TCGA database, the expression and prognosis of LINC00942 were analyzed in LUAD tissues. Then, si-LINC00942 was transfected into A549 and H1299 cells to knockdown the expression of LINC00942. Cell viability was detected by MTT assay. Flow cytometry was used to analyze cell apoptosis. The expressions of PCNA, Bax, Bcl-2, and wnt/β-catenin pathway proteins were detected by western blotting. Dual-luciferase reporter assay was used to evaluate the regulatory relationship between LINC00942 and miR-5006-5p, or miR-5006-5p and FZD1. Results: We discovered that LINC00942 was up-regulated in LUAD tissues compared with adjacent tissues. Besides, we found the increased LINC00942 expression was associated with poor survival. In addition, silencing of LINC00942 suppressed the proliferation, migration, invasion and facilitated the apoptosis of A549 and H1299 cells. Moreover, silencing of LINC00942 repressed the expression of PCNA, Bcl-2, and enhanced Bax expression in A549 and H1299 cells. Mechanically, LINC00942 exerted its effects via enhancing Wnt signaling. LINC00942 functioned as competing endogenous RNA (ceRNA) by binding to miR-5006-5p, upregulating the expression of FZD1, which was a direct target of miR-5006-5p. Conclusion: Our findings indicated that LINC00942/miR-5006-5p/FZD1 axis played important roles in LUAD growth through enhancing Wnt signaling. LINC00942/miR-5006-5p/FZD1 axis might serve as a potential biomarker and therapeutic target for LUAD treatment.

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NLRP3 is a Novel Prognostic Biomarker and Correlates With Immune Infiltrates in Lung Adenocarcinoma and Skin Cutaneous Melanoma

10.21203/rs.3.rs-880002/v1 ◽

2021 ◽

Author(s):

Chenxi Yuan ◽

Qingwei Wang ◽

Xueting Dai ◽

Yipeng Song ◽

Jinming Yu

Keyword(s):

Logistic Regression ◽

Regression Analysis ◽

Lung Adenocarcinoma ◽

Immune Cells ◽

Cutaneous Melanoma ◽

Cox Regression ◽

Cox Regression Analysis ◽

Potential Biomarker ◽

The Impact ◽

Nlrp3 Expression

Abstract Background: Lung adenocarcinoma (LUAD) and skin cutaneous melanoma (SKCM) are common tumors around the world. However, the prognosis in advanced patients is poor. Because NLRP3 was not extensively studied in cancers, so that we aimed to identify the impact of NLRP3 on LUAD and SKCM through bioinformatics analyses. Methods: TCGA and TIMER database were utilized in this study. We compared the expression of NLRP3 in different cancers and evaluated its influence on survival of LUAD and SKCM patients. The correlations between clinical information and NLRP3 expression were analyzed using logistic regression. Clinicopathologic characteristics associated with overall survival in were analyzed by Cox regression. In addition, we explored the correlation between NLRP3 and immune infiltrates. GSEA and co-expressed gene with NLRP3 were also done in this study. Results: NLRP3 expressed disparately in tumor tissues and normal tissues. Cox regression analysis indicated that up-regulated NLRP3 was an independent prognostic factor for good prognosis in LUAD and SKCM. Logistic regression analysis showed increased NLRP3 expression was significantly correlated with favorable clinicopathologic parameters such as no lymph node invasion and no distant metastasis. Specifically, a positive correlation between increased NLRP3 expression and immune infiltrating level of various immune cells was observed. Conclusion: Together with all these findings, increased NLRP3 expression correlates with favorable prognosis and increased proportion of immune cells in LUAD and SKCM. These conclusions indicate that NLRP3 can serve as a potential biomarker for evaluating prognosis and immune infiltration level.

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Erythropoietin Receptor is a Risk Factor for Prognosis: A Potential Biomarker in Lung Adenocarcinoma

10.21203/rs.3.rs-1211017/v1 ◽

2022 ◽

Author(s):

Ya-Jing Zhang ◽

Sen-Yu Wang ◽

Song-Tao Han ◽

Yao-Yao Huang ◽

Yang-Chun Feng

Keyword(s):

Lung Adenocarcinoma ◽

Gene Mutations ◽

Predictive Ability ◽

Erythropoietin Receptor ◽

Immunohistochemical Method ◽

Normal Lung ◽

Mrna Levels ◽

Protein Levels ◽

Potential Biomarker ◽

Epor Expression

Abstract Background: Lung cancer has the highest mortality rate of all cancers, and LUAD's survival rate is particularly poor. Erythropoietin receptor (EPOR) is a member of the cytokine class I receptor family and can be detected in cancers such as lung adenocarcinoma (LUAD), however, the expression levels and prognostic value of EPOR in LUAD are still unclear.Methods: Multiple bioinformatics databases such as TIMER, Kaplan-Meier Plotter and TCGA databases, immunohistochemical method, and clinicopathological data of 92 LUADpatients between January 2008 and June 2016 were used to explore the EPOR expression, gene mutations affecting EPOR expression, EPOR-interacting or coexpressed genes, potential biological functions and the correlation of EPOR expression with prognosis, immune microenvironment and so on.All statistical analyses were performed in the R version 4.1.1.Results: In this study, the EPOR mRNA expression in LUAD tissues was possibly downregulated compared with that in normal lung tissues, but the EPOR protein expression in LUAD tissues was higher than that in paired normal lung tissues. Mutations in five genes, DDX60L, LGR6, POTEB3, RIF1 and SOX5, resulted in downregulation of EPOR expression, mutations in 10 genes includingC1orf168, DBX2 and EIF5B, resulted in upregulation of EPOR expression. Erichment analyses showed that EPOR is involved in neural tissue ligand-receptor interactions, MAPK and PI3K/Akt signaling pathways and cancer pathways. The KM Plotter and PrognoScan databases consistently concluded that EPOR was associated with prognosis in LUAD patients. Our clinicopathological data showed that high EPOR expression was associated with poorer OS (29.5 vs 46 months) and had a good predictive ability for 5-year survival probability. Conclusions: EPOR expression might be downregulated at the mRNA levels and significantly upregulated at the protein levels in LUAD, which showed that the mRNA and protein levels of EPOR are inconsistent.The high expression of EPOR was associated with poor prognosis and is expected to be a potential new prognostic marker for LUAD.

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ERO1L shapes the immune-suppressive tumor microenvironment and is a potential biomarker for immunotherapy response in lung adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21006 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21006-e21006

Author(s):

Lihui Liu ◽

Chao Wang ◽

Sini Li ◽

Pei Xue ◽

Hua Bai ◽

...

Keyword(s):

T Cells ◽

Endoplasmic Reticulum ◽

Lung Adenocarcinoma ◽

Signaling Pathways ◽

Survival Data ◽

Checkpoint Inhibitors ◽

Q Value ◽

Immune Infiltration ◽

Potential Biomarker

e21006 Background: Recently, immune checkpoint inhibitors have led to a paradigm shift in treatment for patients with lung adenocarcinoma (LUAD), however, the identification of biomarkers to enable patient selection is urgently required. The endoplasmic reticulum oxidoreductin-1-like ( ERO1L) gene encodes an endoplasmic reticulum luminal localized glycoprotein known to associated with hypoxia. The role of ERO1L in the crafting of the tumor immune microenvironment (TIME) is yet to be elucidated. Methods: In this study, raw datasets (including RNA-seq, methylation, sgRNA-seq, phenotype, and survival data) were obtained from public databases. This data was analyzed and used to explore the biological landscape of ERO1L in immune infiltration. Expression data was used to characterize samples. Using gene signatures and cell quantification, stromal and immune infiltration was determined. These findings were used to predict sensitivity to immunotherapy. Results: We identified ERO1L to be an oncogene, the mRNA expression of which is significantly higher in LUAD compared with normal tissues. High expression levels of ERO1L were associated with poor prognoses in terms of overall survival (HR: 1.52, 95% CI: 1.27-1.82) and progression-free survival (HR: 1.93, 95% CI: 1.47-2.53). This overexpression was found to be a result of hypomethylation of the ERO1L promoter. Overexpression of ERO1L resulted in an immune-suppressive TIME via the recruitment of immune-suppressive cells including regulatory T cells (Spearman’s ρ = 0.199, p < 0.001) cancer associated fibroblasts (ρ = 0.286, p < 0.001), and myeloid-derived suppressor cells (ρ = 0.423, p < 0.001), and also indicated the polarization of M1-type to M2-type macrophage. On the contrary, overexpression of ERO1L was closely associated with deficiency of immune-active cells including B cells (ρ = -0.250, p < 0.001), CD8+ T cells (ρ = -0.299, p < 0.001), and NK cells (ρ = -0.258, p < 0.001). Using the Tumor Immune Dysfunction and Exclusion (TIDE) framework, it was identified that patients in the ERO1Lhigh group possessed a significantly lower response rate (31.0%) to immunotherapy compared with the ERO1Llow group (86.0%). Mechanistic analysis revealed that overexpression of ERO1L was associated with the upregulation of JAK-STAT (NES = 1.65, FDR q-value = 0.0) and NF-κB (NES = 2.03, FDR q-value = 0.0) signaling pathways, thus affecting chemokine and cytokine patterns in the TIME. Conclusions: Our study provides clear insight into the potential role of ERO1L in tumor immunology. Overexpression of ERO1L was indicative of a hypoxia-induced immune-suppressive TIME, which was shown to confer resistance to immunotherapy in patients with LUAD. ERO1L was shown to mediate cytokine and chemokine patterns in the TIME, which were resulted from activations of JAK-STAT and NF-κB signaling pathways.

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Establishment of Immune-related Gene Pair Signature to Predict Lung Adenocarcinoma Prognosis

Cell Transplantation ◽

10.1177/0963689720977131 ◽

2020 ◽

Vol 29 ◽

pp. 096368972097713

Author(s):

Xueping Jiang ◽

Yanping Gao ◽

Nannan Zhang ◽

Cheng Yuan ◽

Yuan Luo ◽

...

Keyword(s):

High Risk ◽

Lung Adenocarcinoma ◽

Gene Pair ◽

Risk Group ◽

High Risk Group ◽

Gene Set Enrichment Analysis ◽

M2 Macrophage ◽

Related Gene ◽

Immune Related Gene ◽

Potential Biomarker

Tumor microenvironment (TME) has critical impacts on the pathogenesis of lung adenocarcinoma (LUAD). However, the molecular mechanism of TME effects on the prognosis of LUAD patients remains unclear. Our study aimed to establish an immune-related gene pair (IRGP) model for prognosis prediction and internal mechanism investigation. Based on 702 TME-related differentially expressed genes (DEGs) extracted from The Cancer Genome Atlas (TCGA) training cohort using the ESTIMATE algorithm, a 10-IRGP signature was established to predict LUAD patient prognosis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that DEGs were significantly associated with tumor immune response. In both TCGA training and Gene Expression Omnibus validation datasets, the risk score was an independent prognostic factor for LUAD patients using Lasso-Cox analysis, and patients in the high-risk group had poorer prognosis than those in the low-risk one. In the high-risk group, M2 macrophage and neutrophil infiltrations were higher, while the levels of T cell follicular helpers were significantly lower. The gene set enrichment analysis results showed that DNA repair signaling pathways were involved. In summary, we established an IRGP signature as a potential biomarker to predict the prognosis of LUAD patients.

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Baseline Plasma EGFR Circulating Tumour DNA Levels in a Pilot Cohort of EGFR-Mutant Limited-Stage Lung Adenocarcinoma Patients Undergoing Radical Lung Radiotherapy

Case Reports in Oncology ◽

10.1159/000508932 ◽

2020 ◽

Vol 13 (2) ◽

pp. 896-903

Author(s):

Brendan Seng Hup Chia ◽

Wen Long Nei ◽

Sabanayagam Charumathi ◽

Kam Weng Fong ◽

Min-Han Tan

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Cancer Patients ◽

Early Stage ◽

Early Stage Disease ◽

Lung Cancer Patients ◽

Limited Stage ◽

Potential Biomarker ◽

Egfr Mutant

The use of circulating cell-free tumour DNA (ctDNA) is established in metastatic lung adenocarcinoma to detect and monitor sensitising EGFR mutations. In early-stage disease, there is very little data supporting its role as a potential biomarker. We report on a prospective cohort of 9 limited-stage EGFR mutant lung cancer patients who were treated with radical radiotherapy. We looked at baseline plasma EGFR ctDNA and noted the detection rates to be higher in locally advanced disease. At a median follow-up of 13.5 months, an association between a detectable pre-radiotherapy plasma EGFR ctDNA and early tumour relapse (155 days vs. NR, p = 0.004) was noted. One patient with persistent plasma EGFR ctDNA predated radiological progression. The role of ctDNA in early-stage lung cancer is developing. Plasma EGFR ctDNA could be a useful biomarker in lung cancer patients undergoing radical treatments for staging, prognostication, and follow-up. These preliminary findings should be explored in larger studies.

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