Comprehensive analysis of a novel signature incorporating lipid metabolism and immune-related genes for assessing prognosis and immune landscape in lung adenocarcinoma.

Background: As the crosstalk between metabolism and antitumor immunity continues to be unraveled, we aim to develop a prognostic gene signature that integrates lipid metabolism and immune features for patients with lung adenocarcinoma (LUAD). Methods: First, differentially expressed genes (DEGs) related to lipid metabolism in LUAD were detected, and subgroups of LUAD patients were identified via the unsupervised clustering method. Based on lipid metabolism and immune-related DEGs, variables were determined by the univariate Cox and LASSO regression, and a prognostic signature was established. The prognostic value of the signature was evaluated by the Kaplan-Meier method, time-dependent ROC, and univariate and multivariate analyses. Five independent GEO datasets were employed for external validation. Gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analysis were performed to investigate the underlying mechanisms. The sensitivity to common chemotherapeutic drugs was estimated based on the GDSC database. Finally, we selected PSMC1 involved in the signature, which has not been reported in LUAD, for further experimental validation. Results: LUAD patients with different lipid metabolism patterns exhibited significant differences in overall survival and immune infiltration levels. The prognostic signature incorporated 10 genes and stratified patients into high- and low-risk groups by median value splitting. The areas under the ROC curves were 0.69 (1-year), 0.72 (3-year), 0.74 (5-year), and 0.74 (10-year). The Kaplan-Meier survival analysis revealed a significantly poorer overall survival in the high-risk group in the TCGA cohort (p < 0.001). In addition, both univariate and multivariate Cox regression analyses indicated that the prognostic model was the individual factor affecting the overall survival of LUAD patients. Through GSEA and GSVA, we found that tumor progression and inflammatory and immune-related pathways were enriched in the high-risk group. Additionally, patients with high-risk scores showed higher sensitivity to chemotherapeutic drugs. The in vitro experiments further confirmed that PSMC1 could promote the proliferation and migration of LUAD cells. Conclusions: We developed and validated a novel signature incorporating both lipid metabolism and immune-related genes for all-stage LUAD patients. This signature can be applied not only for survival prediction but also for guiding personalized chemotherapy and immunotherapy regimens.

Prognostic value of the ferroptosis-related gene SLC2A3 in gastric cancer and related immune mechanisms.

SLC2A3 is a ferroptosis marker engaged in transmembrane glucose transport. However, the effect of SLC2A3 on the prognosis of patients with cancer remains unclear. This study aimed to explore the prognostic implications of SLC2A3 and its underlying immune mechanisms in gastric cancer. The mRNA expression profiles and corresponding clinical data of patients with gastric cancer were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Differentially expressed genes related to SLC2A3 were identified using the R package "limma." Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, gene set enrichment analysis, and gene set variation analysis were used to explore the underlying mechanisms. The protein-protein and miRNA interaction networks were analyzed using Cytoscape software. Immune cell infiltration was assessed using single-sample gene set enrichment analysis. Univariate and multivariate Cox regression analyses revealed the relationship between SLC2A3 expression and prognosis. SLC2A3 was found to be highly expressed in tumor tissues and was associated with an unfavorable prognosis in patients with gastric cancer. Functional enrichment analysis showed that SLC2A3 is related to cytokine-cytokine receptor interaction, epithelial-mesenchymal transition, T cell receptor signaling pathway, B cell receptor signaling pathway, and immune checkpoints. SLC2A3 is also involved in immune response regulation and is regulated by multiple miRNAs, including miR-195-5p, miR-106a-5p, miR-424-5p, and miR-16-5p. Univariate and multivariate Cox regression analyses indicated that SLC2A3 can be used as an independent prognostic factor for predicting the outcome in patients with gastric cancer. SLC2A3 and related miRNAs are potential prognostic biomarkers and therapeutic targets.

Identification of GGT5 as a Novel Prognostic Biomarker for Gastric Cancer and its Correlation With Immune Cell Infiltration.

Gastric cancer (GC) is a common malignant tumor of the digestive system. Recent studies revealed that high gamma-glutamyl-transferase 5 (GGT5) expression was associated with a poor prognosis of gastric cancer patients. In the present study, we aimed to confirm the expression and prognostic value of GGT5 and its correlation with immune cell infiltration in gastric cancer. First, we compared the differential expression of GGT5 between gastric cancer tissues and normal gastric mucosa in the cancer genome atlas (TCGA) and GEO NCBI databases using the most widely available data. Then, the Kaplan-Meier method, Cox regression, and univariate logistic regression were applied to explore the relationships between GGT5 and clinical characteristics. We also investigated the correlation of GGT5 with immune cell infiltration, immune-related genes, and immune checkpoint genes. Finally, we estimated enrichment of gene ontologies categories and relevant signaling pathways using GO annotations, KEGG, and GSEA pathway data. The results showed that GGT5 was upregulated in gastric cancer tissues compared to normal tissues. High GGT5 expression was significantly associated with T stage, histological type, and histologic grade (p < 0.05). Moreover, gastric cancer patients with high GGT5 expression showed worse 10-years overall survival (p = 0.008) and progression-free intervals (p = 0.006) than those with low GGT5 expression. Multivariate analysis suggested that high expression of GGT5 was an independent risk factor related to the worse overall survival of gastric cancer patients. A nomogram model for predicting the overall survival of GC was constructed and computationally validated. GGT5 expression was positively correlated with the infiltration of natural killer cells, macrophages, and dendritic cells but negatively correlated with Th17 infiltration. Additionally, we found that GGT5 was positively co-expressed with immune-related genes and immune checkpoint genes. Functional analysis revealed that differentially expressed genes relative to GGT5 were mainly involved in the biological processes of immune and inflammatory responses. In conclusion, GGT5 may serve as a promising prognostic biomarker and a potential immunological therapeutic target for GC, since it is associated with immune cell infiltration in the tumor microenvironment.

A Novel Predictive Model Incorporating Ferroptosis-Related Gene Signatures for Overall Survival in Patients with Lung Adenocarcinoma.

BACKGROUND Lung adenocarcinoma (LUAD) is the predominant histological type of lung cancer with high morbidity and mortality. Ferroptosis is regarded as a new pattern of programmed cell death concerned with the progression of lung cancer characterized by lipid peroxidation. Nevertheless, the prognostic role of ferroptosis-related genes for LUAD warrant to be explored. MATERIAL AND METHODS RNA sequencing and relevant clinical patient data were obtained from public-access databanks. A prognostic model was constructed through the LASSO Cox regression in the cancer genome atlas cohort. The diagnostic value of the prognostic model was further evaluated in the gene expression omnibus cohort. RESULTS Most of the ferroptosis-related genes (69.9%) were differentially expressed between tumor and adjacent non-cancerous tissues. 43 differentially expressed genes showed a close association with the prognosis of LUAD patients (adjusted p-value <0.05). An 18-gene signature was built and applied to assign patients into high vs low-risk groups. Compared with the high-risk group, patients defined as the low-risk group suffered significantly prolonged OS. Both uni- and multivariate analyses demonstrated that the signature-based score served as a crucial role in influencing the OS of LUAD patients (hazard ratio >1, p<0.001). The immunity-related signaling pathway was enriched in the functional analysis and the infiltration of the immune cells showed a great difference between groups. CONCLUSIONS The predictive model could be applied for prognostic prediction for LUAD. Targeting ferroptosis could be a possible curative strategy against LUAD, and immunomodulation may be one of the potential mechanisms.

Sanguinarine Represses the Growth and Metastasis of Non-small Cell Lung Cancer by Facilitating Ferroptosis.

OBJECTIVE: Ethnopharmacological relevance: Sanguinarine (SAG), a natural benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis Linn. (Bloodroot), possesses a potential anticancer activity. Lung carcinoma is the chief cause of malignancy-related mortality in China. Non-small cell lung carcinoma (NSCLC) is the main subtype of lung carcinoma and accounts for about eighty-five percent of this disease. Current treatment in controlling and curing NSCLC remains deficient. AIM: The role and underlying mechanism of SAG in repressing the growth and metastasis of NSCLC were explored. MATERIALS AND METHODS: The role of SAG in regulating the proliferation and invasion of NSCLC cells was evaluated in vitro and in a xenograft model. After treatment with SAG, Fe2+ concentration, reactive oxygen species (ROS) levels, malondialdehyde (MDA), and glutathione (GSH) content in NSCLC cells were assessed to evaluate the effect of SAG on facilitating ferroptosis. RESULTS: SAG exhibited a dose- and time-dependent cytotoxicity in A549 and H3122 cells. SAG treatment effectively repressed the growth and metastasis of NSCLC in a xenograft model. We, for the first time, verified that SAG triggered ferroptosis of NSCLC cells, as evidenced by increased Fe2+ concentration, ROS level, and MDA content, and decreased GSH content. Mechanistically, SAG decreased the protein stability of glutathione peroxide 4 (GPX4) through E3 ligase STUB1-mediated ubiquitination and degradation of endogenous GPX4. GPX4 overexpression restored the proliferation and invasion of NSCLC cells treated with SAG through inhibiting ferroptosis. CONCLUSION: SAG inhibits the growth and metastasis of NSCLC by regulating STUB1/GPX4-dependent ferroptosis.

The Efficacy of Long-Term Chinese Herbal Medicine Use on Lung Cancer Survival Time: A Retrospective Two-Center Cohort Study with Propensity Score Matching.

OBJECTIVE: To explore the efficacy of long-term use of Chinese herbal medicine (CHM) on survival time of lung cancer. METHODS: We conducted a retrospective cohort study on lung cancer patients. A propensity score matching (PSM) was performed to balance the covariates. Progression-free survival (PFS) was the primary endpoint and overall survival (OS) was the secondary endpoint. Patients who received CHM therapy from the initial date of diagnosis of lung cancer were included in the CHM group. Patients who were not treated with CHM during the same interval were categorized in the control group. A Cox regression model was used to explore the prognostic factors related to lung cancer. Hazard ratios of different subgroups were also analyzed. RESULTS: A total of 1134 patients were included in our study: 761 patients were in the CHM group and 373 patients were in the control group. After PSM, the mPFS and mOS in the CHM group were 70.4 months and 129.1 months, respectively, while the mPFS and mOS in the control group were 23.8 months and 99.7 months, respectively. The results of survival analysis on each stage demonstrated that patients may benefit from the long-term CHM treatment especially for patients with early stage. One-year to ten-year progression-free survival rates in the CHM group were higher than those in the control group (p < 0.001). COX multivariate regression analysis indicated that CHM treatment, female, low age at diagnosis, early tumor stage, and surgery were independent protective factors against recurrence and metastasis of lung cancer. Subgroup analysis showed that CHM treatment could reduce the risk of recurrence and metastasis in each subgroup (p < 0.01). CONCLUSION: Long-term CHM treatment with the Fuzheng Quxie Formula, which can be flexibly applied in the course of lung cancer treatment, not only has a positive influence on the progression-free survival time of lung cancer patients, but also reduces the risk of recurrence and metastasis of lung cancer.

Identification of prognostic markers for hepatocellular carcinoma based on the epithelial-mesenchymal transition-related gene BIRC5.

BACKGROUND: The baculoviral IAP repeat containing 5 (BIRC5) related to epithelial-mesenchymal transition (EMT) plays a crucial role in the pathogenesis of hepatocellular carcinoma (HCC). However, it remains unclear whether BIRC5-related genes can be used as prognostic markers of HCC. METHODS: Kaplan-Meier (K-M) survival curve was used to assess the Overall Survival (OS) of high- and low-expression group divided by the median of BIRC5 expression. The differentially expressed genes (DEGs) between the two groups were screened using the limma package, and performed the functional enrichment analysis by the clusterProfiler package. WGCNA was used to analyze the relationship of the module and the clinical traits. The risk signature was constructed by univariate and multivariate Cox regression analyses and the enrichment analysis of genes in the risk signature was performed by the Intelligent pathway analysis (IPA). The immunophenoscore (IPS) and the tumor immune dysfunction and exclusion (TIDE) were used to estimate the clinical significance of the risk groups. RESULTS: BIRC5 was high-expressed in HCC samples and associated with a poor prognosis (p-value < 0.0001). WGCNA screened 180 module genes which were overlapped with the 241 DEGs, ultimately getting 33 candidate genes. After the Cox regression analyses, CENPA, CDCA8, EZH2, KIF20A, KPNA2, CCNB1, KIF18B and MCM4 were preserved and used to construct risk signature, followed by calculating the risk score. The patients in high-risk groups stratified by median of the risk score were associated with a poor prognosis. The risk score had high accuracy [the area under the curve (AUC) > 0.72] and was closely associated with clinicopathological characteristics of HCC patients. IPA suggested that the 8 genes were enriched in Cancer and Immunological disease related pathways. IPS and TIDE score indicated that the genes in low-risk group could cause an immune response, and patients in the low-risk group may be more sensitive to the immune checkpoint blockade (ICB) therapy. CONCLUSION: The risk score constructed by the 8 genes could not only predict the clinical outcome but also distinguish the cohort of ICB therapy in HCC, which exerted a vital value in treatment and prognosis of HCC.

Chinese Herbal Prescription Fu-Zheng-Qu-Xie Prevents Recurrence and Metastasis of Postoperative Early-Stage Lung Adenocarcinoma: A Prospective Cohort Study Followed with Potential Mechanism Exploration.

Chinese herbal Fu-Zheng-Qu-Xie (FZQX) prescription has been found to improve the immune function and survival of patients with early-stage lung cancer. However, the therapeutic efficacy needs to be evaluated objectively, and the precise mechanism remains unclear. In the present study, a double-center, prospective cohort study was carried out to assess the clinical efficacy of the FZQX prescription in preventing the recurrence and metastasis of postoperative early-stage lung adenocarcinoma. Our results indicated that the FZQX prescription could significantly reduce the 3-year postoperative recurrence rate and improve the life quality. Moreover, the peripheral blood indices showed that the positive immune index (CD4 +T/CD8 +T) increased and the negative immune indices (CD8 +T, Myeloid-derived suppressor cells (MDSCs), Treg) decreased after treatment with the FZQX prescription. Since the positive regulatory effect of the FZQX prescription on immune function, a series of experiments were conducted to verify the tumor-suppressive effect and elucidate the underlying mechanisms. Through the MDSC clearance xenograft model, we confirmed that the FZQX prescription could effectively suppress tumor growth with lesser side effects in vivo, and MDSCs may be involved in the biological process of the FZQX prescription's intervention in lung cancer progression. By establishing the coculture system of MDSCs/LLC to simulate the immune microenvironment of lung cancer, the tumor suppression effect of the FZQX prescription was further validated by in vitro experiments. Besides, it was confirmed that the FZQX prescription could regulate MDSCs to remodel the immunosuppressive tumor microenvironment, thus exerting its preventive effect on relapse of lung cancer. Finally, the pathway activator and inhibitor were further used to explore the potential molecular mechanism. Results demonstrated that the IL-1ß/NF-κB signaling pathway was one of the critical signaling pathways of FZQX prescription regulating MDSCs to prevent the recurrence and metastasis of lung adenocarcinoma.

Mechanism of Sanguinarine in Inhibiting Macrophages to Promote Metastasis and Proliferation of Lung Cancer via Modulating the Exosomes in A549 Cells.

OBJECTIVE: Sanguinarine (SNG) is a benzophenanthridine alkaloid obtained from the roots of Sanguinaria canadensis and has an anticancer effect. The aim of this study was to explore the mechanism of SNG in inhibiting macrophages via regulating the exosomes derived from lung carcinoma cells to reduce metastasis and proliferation of lung carcinoma. METHODS: Human lung cancer cells (A549 cells) were treated with 4µM of SNG. Exosomes of A549 cells were extracted from A549 cells supernatant, and THP-1 cells were cultured with exosomes. Then, the supernatant of THP-1 cells was collected and cultured with A549 cells. Cell proliferation was measured via plate clone formation and CCK-8 assays. Migration was assessed by using Transwell assay and scratch test. Cellular invasion was detected by Transwell assay. Apoptosis was determined using flow cytometry. Moreover, the protein expressions of GAPDH, P65 and P-P65 in THP-1 cells were measured by Western blot. Levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and chemotactic cytokines ligand 2 (CCL-2) extracted from THP-1 cells were determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Compared to the control group, exosomes could activate THP-1 cells, and the invasion, migration, and proliferation of A549 cells were consequently enhanced. Exosomes could increase the protein expression of p-p65 and the RNA expression levels of TNF-α, IL-6, and CCL-2 in THP-1 cells. Compared with the exosome group, SNG-treated exosomes inhibited THP-1 cells so that the invasion, proliferation, and migration of A549 cells were attenuated and apoptosis was promoted. In THP-1 cells, SNG-treated exosomes inhibited P-P65 expression and the RNA expression levels of TNF-α, IL-6, and CCL-2. CONCLUSION: Exosomes treated by SNG inhibited THP-1 cells so that the invasion, proliferation, and migration of A549 cells were inhibited, and the apoptosis was promoted. The mechanism is possibly associated with the inhibition of NF-κB pathway in THP-1 cells.

ShenQi FuZheng Injection combined with chemotherapy in the treatment of colorectal cancer: A meta-analysis.

OBJECTIVE: This study aims to investigate cellular immunity and clinical efficacy of ShenQi FuZheng Injection (SFI) in the associated chemotherapy of colorectal cancer (CRC). METHODS: PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Full-text Database (VIP), WanFang Database and Chinese Biomedical Literature Database (CBM) searches were undertaken to identify randomized controlled trials of SFI plus chemotherapy versus chemotherapy alone in CRC patients. The quality of each trial was assessed according to the Jadad's scale, and Review Manager 5 was used to statisitically analyze the outcomes. RESULTS: Eight studies involving 722 patients were included in this review. The meta-analyses suggested there was a significantly higher overall response rate (OR 1.89; CI: 1.10-3.24; p = 0.02), grades of KPS (OR 2.35; CI: 1.55-3.56; p<0.01), CD3+cells (MD 10.29; CI: 8.46-12.12; p<0.01), CD4+cells (MD 7.06; CI: 5.33-8.794; p<0.01), CD4/CD8+cells (MD 0.32; CI: 0.25-0.40; p<0.01), NK+ (MD 7.20; CI: 2.02-12.37, p = 0.006), WBC (MD 1.24; CI: 0.59-1.89; p<0.01), HB (MD 14.55; CI: 7.47-21.63; p<0.01), and PLT (MD 19.05; CI: 4.29-33.81; p = 0.01), but lower severe toxicity for leukocytopenia (OR 0.37; CI: 0.17-0.80; p = 0.01), thrombocytopenia (OR 0.32; CI: 0.14-0.74; p = 0.008), gastrointestinal toxicity (OR 0.48; CI: 0.24-0.96; p = 0.04), when chemotherapy combined with SFI was compared with chemotherapy alone. There were similarities between two groups in liver dysfunction (OR 0.44; CI: 0.18-1.08; p = 0.07) and CD8+ (MD 0.54; CI: -1.89-2.96; p = 0.66). Also, there was presence of heterogeneity in the CD8 results; after the sensitivity analysis, the result of CD8+ was reversed (MD 1.57; CI: 0.32-2.81; p = 0.01). There was no significant publication bias across studies according to the Egger's (P = 0.19) and Begg's test (P = 0.23). CONCLUSION: SFI enhances chemotherapy efficiency as they are combined and used in the treatment of colorectal cancer patients. At the same time, SFI also improves patients' immunity function.