Combined detection of estrogen and tumor markers is an important reference factor in the diagnosis and prognosis of lung cancer.

The correlation between lung cancer tumor markers and sex differences in lung cancer remains a clinical problem that is worthy of further study. This study investigated the significance of the combined detection of 17ß-estrogen (E2) and tumor markers in the diagnosis and prognosis of lung cancer. A total of 174 patients, including 117 patients with non-small-cell lung cancer (NSCLC) and 57 patients with benign pulmonary lesions (BPL), were enrolled. An enzyme-linked immunosorbent assay was used to detect the expression of E2, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) in patients with NSCLC and BPL to analyze the correlation between E2 and CEA, NSE or CYFRA21-1 expression, and its correlation with clinicopathological features and prognosis. The expression of tumor markers was then examined in different lung cancer cells (A549, H1795, H460, and SK-MES-1). The expression of tumor markers was detected by a real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. The expressions of p-p44/42 mitogen-activated protein kinase (MAPK) and phospho-AKT (p-AKT) were detected by Western blot analysis. The expression levels of E2, CEA, NSE, and CYFRA21-1 in patients with NSCLC were significantly higher than those in patients with BPL ( P < .05); E2 was positively correlated with tumor markers ( P < .01). Patients with a high expression of E2 and tumor markers showed a poor prognosis ( P < .05). RT-quantitative PCR and Western blot analysis showed that the expression levels of CEA, NSE, CYFRA21-1, p-p44/42 MAPK, and p-AKT in the E2 group were higher than those in the other groups ( P < .05). These studies indicate that the interaction of E2 and tumor markers can significantly improve the role of tumor markers in the diagnosis and prognosis of lung cancer.

Interaction of estrogen receptor ß5 and interleukin 6 receptor in the progression of non-small cell lung cancer.

Numerous studies have shown that the estrogen receptor beta (ERß) and interleukin 6 receptor (IL-6R) had interaction in many tumors, including lung cancer. Previous studies found that ERß5 exhibits a different biological function compared with the other subtypes of ERß. Therefore, this study mainly explores the interaction between ERß5 and IL-6R in the progression of lung cancer. We found that the expression of ERß5, IL-6 and glycoprotein 130 (GP130) were significantly increased (P < 0.001) and the 5-year survival rate with the co-expression of ERß5 and GP130 is significantly lower (P = 0.0315) in non-small cell lung cancer (NSCLC) patients. The cell proliferation, invasion, and cell cycle were markedly increased, and the cell apoptotic was markedly inhibited with the concurrent action of ERß5 and IL-6 in A549 cells (P < 0.05). In addition, the expression of ERß5, GP130, p-AKT, and p-44/42 MAPK was also significantly increased in A549 cells (P < 0.05). These results indicate that ERß5 and GP130 can synergistically promote the progression of NSCLC and maybe combined as an independent prognostic factor in patients. In addition, these results also provide a theoretical basis for the combined targeting therapy of ERß5 and GP130 in NSCLC.

[Research progress on interleukin-6 in lung cancer].

As the core of cellular immunotherapy, T cells are important aspects of research and treatment of lung cancer. IL-6 is a costimulatory signal factor of T cells that is directly targeted by lung cancer stem cells. As a highly expressed cytokine in lung cancer cells, IL-6 plays an important role in variety of biological activities such as tumor occurrence, development, invasion and metastasis. This article reviews the research progress on IL-6 in lung cancer, including cancer development and progression, and the therapeutic sensitivity of lung cancer.

Multicellular ecotypes shape progression of lung adenocarcinoma from ground-glass opacity toward advanced stages.

Lung adenocarcinoma is a type of cancer that exhibits a wide range of clinical radiological manifestations, from ground-glass opacity (GGO) to pure solid nodules, which vary greatly in terms of their biological characteristics. Our current understanding of this heterogeneity is limited. To address this gap, we analyze 58 lung adenocarcinoma patients via machine learning, single-cell RNA sequencing (scRNA-seq), and whole-exome sequencing, and we identify six lung multicellular ecotypes (LMEs) correlating with distinct radiological patterns and cancer cell states. Notably, GGO-associated neoantigens in early-stage cancers are recognized by CD8+ T cells, indicating an immune-active environment, while solid nodules feature an immune-suppressive LME with exhausted CD8+ T cells, driven by specific stromal cells such as CTHCR1+ fibroblasts. This study also highlights EGFR(L858R) neoantigens in GGO samples, suggesting potential CD8+ T cell activation. Our findings offer valuable insights into lung adenocarcinoma heterogeneity, suggesting avenues for targeted therapies in early-stage disease.

Dual network analysis of transcriptome data for discovery of new therapeutic targets in non-small cell lung cancer.

The drug therapy for non-small cell lung cancer (NSCLC) have always been issues of poisonous side effect, acquired drug resistance and narrow applicable population. In this study, we built a novel network analysis method (difference- correlation- enrichment- causality- node), which was based on the difference analysis, Spearman correlation network analysis, biological function analysis and Bayesian causality network analysis to discover new therapeutic target of NSCLC in the sequencing data of BEAS-2B and 7 NSCLC cell lines. Our results showed that, as a proteasome subunit coding gene in the central of cell cycle network, PSMD2 was associated with prognosis and was an independent prognostic factor for NSCLC patients. Knockout of PSMD2 inhibited the proliferation of NSCLC cells by inducing cell cycle arrest, and exhibited marked increase of cell cycle blocking protein p21, p27 and decrease of cell cycle driven protein CDK4, CDK6, CCND1 and CCNE1. IPA and molecular docking suggested bortezomib has stronger affinity to PSMD2 compared with reported targets PSMB1 and PSMB5. In vitro and In vivo experiments demonstrated the inhibitory effect of bortezomib in NSCLC with different driven mutations or with tyrosine kinase inhibitors resistance. Taken together, bortezomib could target PSMD2, PSMB1 and PSMB5 to inhibit the proteasome degradation of cell cycle check points, to block cell proliferation of NSCLC, which was potential optional drug for NSCLC patients.

A Novel Immune-Prognosis Index Predicts the Benefit of Lung Adenocarcinoma Patients.

Background: Constructed an immune-prognosis index (IPI) and divided lung adenocarcinoma (LUAD) patients into different subgroups according to IPI score, describe the molecular and immune characteristics of patients between different IPI subgroups, and explore their response to immune checkpoint blockade (ICB) treatment. Methods: Based on the transcriptome profile of LUAD patients in TCGA and immune gene sets from ImmPort and InnateDB, 15 hub immune genes were identified through correlation and Bayesian causal network analysis. Then, IPI was constructed with 5 immune genes by using COX regression analysis and verified with external datasets (GSE30219, GSE37745, GSE68465, GSE126044 and GSE135222). Finally, the characteristics and the response to ICB treatment of LUAD patients between two different IPI subgroups were analyzed. Results: IPI was constructed based on the expression of 5 genes, including A2M, ADRB1, ADRB2, VIPR1 and PTH1R. IPI-high LUAD patients have a better overall survival than IPI-low LUAD patients, consistent with the results in the GEO cohorts. The comprehensive results showed that patients in the IPI-high subgroup were exhibited characters as metabolism-related signaling pathways activation, lower TP53 and TTN mutation rate, more infiltrations of CD8 T cells, dendritic cells and macrophages M1, especially earned more benefit from ICB treatment. In contrast, patients in the IPI-low subgroup were exhibited characters as p53 signaling pathways activation, higher TP53 and TTN mutation rate, more infiltrations of resting memory CD4 T cells, macrophages M2, immune-suppressive response and less benefit from ICB treatment. Conclusion: IPI is a potentially valuable prognostic evaluation method for LUAD, which works well in the benefit predicting of LUAD patients within ICB treatment.

Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance.

Background: Tyrosine kinase inhibitor (TKI) treatment has significantly improved the prognosis of oncogenic-driven lung adenocarcinoma (LUAD). However, drug resistance limits the long-term benefits of patients. Therefore, there is a pressing need to explore the mechanism of TKI resistance and identify new therapeutic targets. It is possible to overcome TKI resistance by inducing tumor cell death through a new process called ferroptosis. Aberrations in ferroptosis, which is a kind of regulated cell death (RCD), has been confirmed to be involved in the development and progression of multiple tumors, and is closely related to patient survival. At present, the role of ferroptosis in TKI resistance remains unclear. Methods: Ferroptosis-related factors were isolated by expression characteristics analysis based on the multi-omics data of LUADs and normal lung tissues from The Cancer Genome Atlas (TCGA) database. Next, expression of selected ferroptosis-related factors and prognosis were analyzed. Subsequently, the differences in the expression of selected ferroptosis-related factors before and after TKI resistance on a variety of LUAD cell lines were analyzed to identify the factors that were involved in TKI resistance. Finally, the therapeutic effects were confirmed in vitro by targeting the selected ferroptosis-related factors with small molecule compounds. Results: Glutathione Peroxidase 4 (GPX4), a ferroptosis-related factor, was up-regulated in tumor tissue of LUADs, and correlated with the prognosis of patients. By detecting the expression change of GPX4 before and after TKI resistance in a variety of LUAD cell lines, we confirmed that the inhibition of GPX4 could overcome epidermal growth factor receptor (EGFR)-TKI resistance by inducing ferroptosis. Conclusions: GPX4 could serve as a novel therapeutic target for EGFR-TKI resistance in LUAD.

Identifies Immune Feature Genes for Prediction of Chemotherapy Benefit in Cancer.

Chemotherapy is still the most fundamental treatment for advanced cancers so far. Previous studies have indicated that immune cell infiltration (ICI) index could serve as a biomarker to predict chemotherapy benefit in breast cancer and colorectal cancer. However, due to different responses of tumor infiltrating immune cells (TIICs) to chemotherapy, the prediction efficiency of ICI index is not fully confirmed by now. In our study, we first extended this conclusion in 7 cancers that high ICI index could certainly indicate chemotherapy benefit (P<0.05). But we also found the fraction of different TIICs and the interaction of TIICs were varies greatly from cancer to cancer. Therefore, we executed correlation and causal network analysis to identify chemotherapy associated immune feature genes, and fortunately identified six co-owned immune feature genes (CD48, GPR65, C3AR1, CD2, CD3E and ARHGAP9) in 10 cancers (BLCA, BRCA, COAD, LUAD, LUSC, OV, PAAD, SKCM, STAD and UCEC). Base on this, we developed a chemotherapy benefit prediction model within six co-owned immune feature genes through random forest classifying (AUC =0.83) in cancers mentioned above, and validated its efficiency in external datasets. In short, our work offers a novel model with a shrinking panel which has the potential to guide optimal chemotherapy in cancer.

Targeting STT3A produces an anti-tumor effect in lung adenocarcinoma by blocking the MAPK and PI3K/AKT signaling pathway.

Background: Glycosylation is crucial for the stability and biological functions of proteins. The aberrant glycosylation of critical proteins plays an important role in multiple cancers, including lung adenocarcinoma (LUAD). STT3 oligosaccharyltransferase complex catalytic subunit A (STT3A) is a major isoform of N-linked glycosyltransferase that catalyzes the glycosylation of various proteins. However, the functions of STT3A in LUAD are still unclear. Methods: The expression profiles of STT3A were initially analyzed in public data sets and then validated by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry assays in clinical LUAD samples. The overall survival (OS) between patients with high and low STT3A expression was compared using a Kaplan-Meier curve with a log-rank analysis. STT3A was knocked-out using CRISPR/Cas9 and inhibited by NGI-1. Cell Counting Kit-8, colony formation assay, wound-healing, transwell assay, and flow cytometry were performed to assess the cellular functions of STT3A in vitro. A mice xenograft model was established to investigate the effects of STT3A on tumor growth in vivo. Further, the downstream signaling pathways of STT3A were screened by mass spectrometry with a bioinformatics analysis, and the activation of the target pathways were subsequently validated by Western blot. Results: The expression of STT3A was frequently upregulated in LUAD tissues than normal lung tissues. The high expression of STT3A was significantly associated with poor OS in LUAD patients. The knockout or inhibition of STT3A suppressed proliferation, migration, and invasion, and arrested the cell cycle of LUAD cell lines in vitro. Similarly, the knockout or inhibition of STT3A suppressed tumor growth in vivo. In terms of molecular mechanism, STT3A may promote LUAD progression by activating the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase and protein kinase B (PI3K/AKT) pathways and regulating the epithelial-mesenchymal transition. Conclusions: STT3A promotes LUAD progression via the MAPK and PI3K/AKT signaling pathways and could serve as a novel prognostic biomarker and potential therapeutic target for LUAD patients.

A six-long noncoding RNA model predicts prognosis in lung adenocarcinoma.

BACKGROUND: The incidence and mortality of lung cancer rank first among various malignant tumors. The lack of clear molecular classification and effective individualized treatment greatly limits the treatment benefits of patients. Long non-coding RNAs (lncRNAs) have been demonstrated widely involve in tumor progressing, and been proved easy to detect for occupying majority in transcriptome. However, less work focuses on studying the potency of lncRNAs as molecular typing and prognostic indicator in lung cancer. METHODS: Based on the 448 lung adenocarcinoma (LUAD) samples and the expression of 14,127 lncRNAs from the Cancer Genome Atlas (TCGA) database, we constructed a co-expression network using weighted gene co-expression network analysis. Then based on the feature module and the overall survival of patients, we constructed a risk score model through Cox proportional hazards regression and verified it with a validation cohort. Finally, according to the median of risk score, the function of this model was enriched. RESULTS: We identified a module containing 123 lncRNAs that is related with the prognosis of LUAD. Using univariate and multivariate Cox proportional hazards regression with lasso regression, six lncRNAs were identified to construct a risk score model. The calculation formula shown as follows: risk score = (-0.3057 × EXPVIM-AS1) + (0.9678 × EXPAC092811.1) + (1.0829 × EXPNFIA-AS1) + (-0.3505 × EXPAL035701.1) + (3.9378 × EXPAC079336.4) + (-0.2810 × EXPAL121790.2). Six-lncRNA model can be used as an independent prognostic indicator in LUAD (P<0.001) and the area under the 5-year receiver operating characteristic (ROC) curve is 0.715. CONCLUSIONS: We developed a six-lncRNA model, which could be used for predicting prognosis and guiding medical treatment in LUAD patients.

Identification of LncRNA Prognostic Markers for Ovarian Cancer by Integration of Co-expression and CeRNA Network.

BACKGROUND: Ovarian cancer (OC), one of the most prevalent gynecological malignancies, is characterized by late detection and dismal prognosis. Recent studies show that long non-coding RNAs (lncRNAs) in competitive endogenous RNA (ceRNA) networks influence immune infiltration and cancer prognosis. However, the function of lncRNA in OC immune infiltration and prognosis remains unclear. METHODS: Transcriptomes of 378 OC samples and clinical data were retrieved from the TCGA repository. Modules related to immune cells were identified using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis and survival analysis were then performed for the identification of immune-related lncRNAs in the brown module using Cox regression model. Finally, a ceRNA network was constructed by using the lncRNAs and mRNAs from the brown module. RESULTS: We found lncRNAs and mRNAs in the brown module to be significantly associated with immune cells in OC and identified 4 lncRNAs as potential OC prognostic markers. We further established that lncRNAs in the ceRNA network influence OC immune infiltration and prognosis by regulating miRNA, ultimately modulating mRNA levels. CONCLUSION: We have identified 4 lncRNAs as independent immune prognostic factors for OC. Furthermore, our findings offer novel insight into lncRNAs as OC immune and prognostic biomarkers.

Overexpression of Ulk2 inhibits proliferation and enhances chemosensitivity to cisplatin in non-small cell lung cancer.

The aim of the present study was to examine the function of unc-51 like autophagy activating kinase 2 (Ulk2) in non-small cell lung cancer (NSCLC). Western blotting was used to analyze the protein expression of Ulk2 in seven pairs of cancerous and adjacent non-cancerous NSCLC specimens. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was used to determine the mRNA expression of Ulk2 in 20 pairs of tumor and adjacent normal tissues. Two NSCLC cell lines, A549 and H460, were transfected with an Ulk2 overexpression plasmid or empty vector; cell proliferation and chemosensitivity were measured using an MTT assay, and flow cytometry and western blotting were used to evaluate apoptosis. A nude mouse tumorigenesis experiment was used to assess tumor volume in vivo, using A549 cells stably overexpressing Ulk2 and control cells. The protein expression levels of Ulk2 were significantly lower in 6/7 (85.7%) cases of NSCLC compared with in non-cancerous tissues, as determined by western blotting (P<0.05). The mRNA expression levels of Ulk2 were significantly lower in 16/20 (70.0%) NSCLC specimens compared with in non-cancerous tissues, as revealed by RT-qPCR (P<0.05). Overexpression of Ulk2 significantly inhibited the proliferation of A549 and H460 cells (P<0.05) and sensitized the NSCLC cell lines to cisplatin- and etoposide-induced inhibition of proliferation, and to cisplatin-induced apoptosis, with a significant difference identified compared with the control group (P<0.05). Overexpression of Ulk2 significantly increased basal autophagy levels in A549 and H460 cells (P<0.05). Thus, Ulk2-induced enhanced chemosensitivity was suggested to be partly mediated through increased autophagy. The overexpression of Ulk2 significantly suppressed tumor volume in vivo (P<0.05). Overexpression of Ulk2 inhibits cancer cell proliferation and enhances chemosensitivity to cisplatin in NSCLC.

Co-expression network analysis identified KIF2C in association with progression and prognosis in lung adenocarcinoma.

Lung cancer is a malignant tumor with high morbidity and mortality, of which 80% is non-small cell lung cancer (NSCLC). And lung adenocarcinoma (LUAD) is the most important and common subtype in the NSCLC. In current study, the microarray data GSE31210 containing LUAD (n= 226) and normal lung tissue (n= 20) was analyzed to identify 965 differentially expressed genes, on which weighted gene co-expression network analysis was performed. Finally, it was confirmed that there was a significant correlation between brown module and LUAD stage. In the significant module, a total of 54 network hub genes were identified, and six of them were also identified as hub genes of the protein-protein interaction network. In validation, KIF2C showed a higher correlation with disease stage than other hub genes (p< 0.001, R2 = 0.955). Functional enrichment suggests that KIF2C is associated with cell mitosis and cell cycle. Combined with clinicopathological parameters, we found that the high expression of KIF2C is closely related to the relapse and tumor stage of LUAD. Survival analysis showed a significant reduction in overall survival in LUAD patients with high expression of KIF2C. Gene set enrichment analysis (GSEA) also showed that the "cell cycle signaling pathway" and "P53 related pathway" were significantly enriched in LUAD samples with high expression of KIF2C (FDR < 0.05). In conclusion, based on the co-expression analysis, KIF2C was identified in the association with progression and prognosis of LUAD, which might refer a poor prognosis probably by regulating cell cycle signaling pathway.

Anastomosis of the thoracic duct and the azygos vein for the treatment of recurrent chylothoraxes.

Thoracic duct ligation is a widely accepted treatment option for chylothorax. This case report describes another treatment approach for recurrent chylothoraxes after thoracic duct ligation. A 40-year-old woman had chylothoraxes after thoracic duct ligation. She underwent a secondary surgery to ligate the thoracic duct. Three days later, the number of chylothoraxes increased compared with presurgery, and we anastomosed the thoracic duct and azygos vein after releasing the thoracic duct ligation. The patient recovered smoothly and was followed up for 2 years. This case shows that anastomosis of the thoracic duct and azygos vein is an alternative surgical approach to treat recurrent chylothoraxes.

Interleukin-6 and insulin-like growth factor-1 synergistically promote the progression of NSCLC.

The signaling pathways of interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1) play an important role in the progression of lung cancer, and this study aimed to explore whether they can synergistically promote the progression of non-small cell lung cancer (NSCLC). We found that IL-6, glycoprotein 130 (GP130), IGF-1 and IGF-1R were highly expressed in NSCLC (p = .000), and there was the correlation between GP130, IGF-1, and IGF-1R (p < .01). The overall survival of patients with the co-expression of GP130 and IGF-1R was significantly shorter (p = .0360). Co-stimulation of IL-6 and IGF-1 resulted in significantly enhanced in cell proliferation, (p < .05), invasion (p < .05), cycle (p < .05), apoptosis (p < .05), and the expression of signal molecules (GP130, IGF-1R, p-AKT, and p-ERK1/2) (all p < .05) in NSCLC cells. This experiment revealed that IL-6 and IGF-1 can synergistically promote the progression of NSCLC. The high expression of GP130 and IGF-1R is an independent risk factor for poor prognosis patients, and it is helpful to find a more accurate target for targeted therapy in NSCLC.

Oestrogen receptor ß5 and epidermal growth factor receptor synergistically promote lung cancer progression.

Oestrogen receptor beta (ERß) and epidermal growth factor receptor (EGFR) pathway can synergistically promote the proliferation, invasion, and metastasis of non-small-cell lung cancer (NSCLC) cells. ERß has five subtypes, and the selective splicing of exon 8 in ERß5 transcription translational phase makes its biological function different from other subtypes. The following study investigates whether ERß5 interacts with EGFR pathway in lung cancer. Briefly, we found that the overexpression of ERß5 and EGFR is associated with poor prognosis and decreased overall survival in NSCLC patients. Furthermore, the effects of ERß5 and EGFR on cell biological behaviour were investigated in vitro. These results indicated that the combination of ERß5 and EGF induces cell proliferation and invasion, while the combination of ERß5 and Gefitinib (EGFR inhibitors, Gef) induces cell apoptosis and promotes cell mitosis in A549 cell line. In addition, the combination of ERß5 and EGF increases the expression of ERß5, EGFR, and p-ERK1/2 in lung cancer cells. To sum up, the obtained results suggest that ERß5 and EGFR synergistically promote the progression of lung cancer by activating MEK/ERK signalling pathway, which provides a theoretical basis for more accurate combined targeted therapy.

Clinical significance of combined detection of interleukin-6 and tumour markers in lung cancer.

Tumour markers play an important role in the early diagnosis and guidance of prognosis of lung cancer. This study focused on the significance of combined monitoring of interleukin (IL)-6 and tumour markers in improving the specificity and sensitivity of lung cancer diagnosis and disease. The expression of IL-6, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE) and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) in serum of patients with non-small cell lung cancer (NSCLC) (n = 138) was significantly higher compared to patients with benign pulmonary lesions (BPL) (n = 60) and was associated with the clinicopathological features of NSCLC patients. The simultaneous increase in the expression of IL-6 and tumour markers worsened the prognosis of patients. Lung cancer cells were grouped into the blank control group, IL-6 group, niclosamide group (IL-6 pathway inhibitor, NIC) and IL-6 + NIC group. The expression of CEA, NSE, CYFRA21-1, p-Erk1/2 and p-AKT in the IL-6 group was significantly higher compared to the other groups. Therefore, the combined detection of IL-6 and tumour markers is critical to improve the specificity and sensitivity of lung cancer diagnosis. This in-depth study not only helped to elucidate the mechanism of how IL-6 promotes lung cancer but also provided new ideas and entry points to resolve the low specificity and sensitivity of lung cancer-related tumour markers.