Endoplasmic Reticulum Membrane Protein Complex Regulates Cancer Stem Cells and is Associated with Sorafenib Resistance in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential. Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC's clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle. Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells' sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1's role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation. Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.

IFIT1 + neutrophil is a causative factor of immunosuppressive features of poorly cohesive carcinoma (PCC).

The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC.

Correlation between hemoglobin and the risk of common malignant tumors: a 1999-2020 retrospective analysis and causal association analysis.

BACKGROUND: The role of hemoglobin (HGB) in common malignant tumors remains unclear. METHODS: A retrospective analysis was conducted to identify the correlation between HGB levels and risk of 15 malignant tumors using 50,085 samples from the National Health and Nutrition Examination Survey. Mendelian Randomization analyses (MRAs) were performed based on genome-wide association study data to assess the causal relationship between HGB levels and these malignant tumors using more than 700,000 samples. The robustness of the MRA results was confirmed through various analytical methods. Fifty-six in-house samples were used to investigate the correlation between HGB levels and the prognosis in prostate cancer (PRCA) using the Kaplan-Meier curve. RESULTS: High HGB levels were associated with a higher risk for patients with cervix cancer, melanoma, and non-melanoma skin cancer (OR > 1.000, p < 0.05). It served as a protective factor for colon cancer, esophagus cancer, stomach cancer, bone cancer, lung cancer, renal cancer, and PRCA (OR < 1.000, p < 0.05). Furthermore, MRAs suggested that elevated HGB levels were correlated with a reduced risk of PRCA (OR = 0.869, p < 0.05), with no significant association observed between this marker and the remaining 14 malignant tumors. No pleiotropy or heterogeneity was found in the ultimate results for MRAs (p-values > 0.05), suggesting the robustness of the results. The results derived from the in-house data revealed a relationship between higher HGB values and a more favorable prognosis in PRCA (p < 0.05). CONCLUSION: High circulating HGB levels may play a protective prognostic role for PRCA and serve as a protective factor against the occurrence of PRCA.

GTSE1: A potential prognostic and diagnostic biomarker in various tumors including lung adenocarcinoma.

OBJECTIVE: This research was aimed to comprehensively investigate the expression levels, diagnostic and prognostic implications, and the relationship with immune infiltration of G2 and S phase-expressed-1 (GTSE1) across 33 tumor types, including lung adenocarcinoma (LUAD), through gene expression profiling. METHODS: GTSE1 mRNA expression data together with clinical information were acquired from Xena database of The Cancer Genome Atlas (TCGA), ArrayExpress, and Gene Expression Omnibus (GEO) database for this study. The Wilcoxon rank-sum test was used to detect differences in GTSE1 expression between groups. The ability of GTSE1 to accurately predict cancer status was evaluated by calculating the area under the curve (AUC) value for the receiver operating characteristic curve. Additionally, we investigated the predictive value of GTSE1 in individuals diagnosed with neoplasms using univariate Cox regression analysis as well as Kaplan-Meier curves. Furthermore, the correlation between GTSE1 expression and levels of immune infiltration was assessed by utilizing the Tumor Immune Estimate Resource (TIMER) database to calculate the Spearman rank correlation coefficient. Finally, the pan-cancer analysis findings were validated by examining the association between GTSE1 expression and prognosis among patients with LUAD. RESULTS: GTSE1 exhibited significantly increased expression levels in a wide range of tumor tissues in contrast with normal tissues (p < 0.05). The expression of GTSE1 in various tumors was associated with clinical features, overall survival, and disease-specific survival (p < 0.05). In immune infiltration analyses, a strong correlation of the level of immune infiltration with the expression of GTSE1 was observed. Furthermore, GTSE1 demonstrated good discriminative and diagnostic value for most tumors. Additional experiments confirmed the relationship between elevated GTSE1 expression and unfavorable prognosis in individuals diagnosed with LUAD. These findings indicated the crucial role of GTSE1 expression level in influencing the development and immune infiltration of different types of tumors. CONCLUSIONS: GTSE1 might be a potential biomarker for the prognosis of pan-cancer. Meanwhile, it represented a promising target for immunotherapy.

The causal relationship between COVID-19 and ten esophageal diseases: a study utilizing Mendelian randomization.

Background: Clinical signs of dysphagia, pancreatic achalasia, and esophagitis have been reported in patients with COVID-19. However, the causal relationship between COVID-19 and esophageal diseases is not clear. Therefore, we utilized Mendelian randomization to explore the potential association between COVID-19 and esophageal diseases. Methods: The summary statistics for a Genome-wide association study (GWAS) were obtained from The COVID-19 Host Genetics Initiative, encompassing four types of COVID-19 as exposure: severe COVID-19, hospitalized COVID-19 versus ambulatory COVID-19, hospitalized COVID-19 versus uninfected, and confirmed COVID-19. Additionally, summary statistics for ten esophageal diseases as outcomes were sourced from the GWAS Catalog and FinnGen databases. Univariate Mendelian randomization (MR) analysis was utilized to thoroughly investigate and validate the potential causal association between COVID-19 and various esophageal conditions, including esophageal varices, Barrett's esophagus, esophagitis, esophageal obstruction, esophageal ulcer, esophageal perforation, gastroesophageal reflux, congenital esophageal malformations, benign esophageal tumors, and esophageal adenocarcinoma. Results: An inverse variance-weighted (IVW) model was utilized for univariate Mendelian randomization (MR) analysis, which revealed that genetic liability in patients with confirmed COVID-19 was associated with esophageal obstruction (OR [95% CI]: 0.5275458 [0.2822400-0.9860563]; p-value = 0.0450699). Furthermore, a suggestive causal association was found between genetic liability and a reduced risk of benign esophageal tumors (OR [95% CI]: 0.2715453 [0.09368493-0.7870724]; p-value = 0.0163510), but with a suggestively increased risk of congenital esophageal malformations (OR [95% CI]: 6.959561 [1.1955828-40.51204]; p-value = 0.03086835). Additionally, genetic liability in hospitalized COVID-19 patients, compared to non-hospitalized COVID-19 patients, was suggestively associated with an increased risk of esophagitis (OR [95% CI]: 1.443859 [1.0890568-1.914252]; p-value = 0.01068201). The reliability of these causal findings is supported by Cochran's Q statistic and the MR-Egger intercept test. Conclusion: The results of this study suggest the existence of a causal relationship between COVID-19 and esophageal diseases, highlighting differing risk effects of COVID-19 on distinct esophageal conditions.

CDK6 is a novel predictive and prognosis biomarker correlated with immune infiltrates in multiple human neoplasms, including small cell lung carcinoma.

The roles of cyclin-dependent kinase 6 (CDK6) in various cancers, including small cell lung carcinoma (SCLC), remain unclear. Here, 111,54 multi-center samples were investigated to determine the expression, clinical significance, and underlying mechanisms of CDK6 in 34 cancers. The area under the curve (AUC), Cox regression analysis, and the Kaplan-Meier curves were used to explore the clinical value of CDK6 in cancers. Gene set enrichment analysis and correlation analysis were performed to detect potential CDK6 mechanisms. CDK6 expression was essential in 24 cancer cell types. Abnormal CDK6 expression was observed in 14 cancer types (e.g., downregulated in breast invasive carcinoma; p < 0.05). CDK6 allowed six cancers to be distinguished from their controls (AUC > 0.750). CDK6 expression was a prognosis marker for 13 cancers (e.g., adrenocortical carcinoma; p < 0.05). CDK6 was correlated with several immune-related signaling pathways and the infiltration levels of certain immune cells (e.g., CD8+ T cells; p < 0.05). Downregulated CDK6 mRNA and protein levels were observed in SCLC (p < 0.05, SMD = - 0.90). CDK6 allowed the identification of SCLC status (AUC = 0.91) and predicted a favorable prognosis for SCLC patients (p < 0.05). CDK6 may be a novel biomarker for the prediction and prognosis of several cancers, including SCLC.

Clinical Significance and Underlying Mechanisms of CELSR3 in Metastatic Prostate Cancer Based on Immunohistochemistry, Data Mining, and In Silico Analysis.

Background: The treatment and survival rate of patients with metastatic prostate cancer (MPCa) remain unsatisfactory. Herein, the authors investigated the clinical value and potential mechanisms of cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) in MPCa to identify novel targets for clinical diagnosis and treatment. Materials and Methods: mRNA microarray and RNA-Seq (n = 1246 samples) data were utilized to estimate CELSR3 expression and to assess its differentiation ability in MPCa. Similar analyses were performed with miRNA-221-3p. Immunohistochemistry performed on clinical samples were used to evaluate the protein expression level of CELSR3 in MPCa. Based on CELSR3 differentially coexpressed genes (DCEGs), enrichment analysis was performed to investigate potential mechanisms of CELSR3 in MPCa. Results: The pooled standard mean difference (SMD) for CELSR3 was 0.80, demonstrating that CELSR3 expression was higher in MPCa than in localized prostate cancer (LPCa). CELSR3 showed moderate potential to distinguish MPCa from LPCa. CELSR3 protein expression was found to be markedly upregulated in MPCa than in LPCa tissues. The authors screened 894 CELSR3 DCEGs, which were notably enriched in the focal adhesion pathway. miRNA-221-3p showed a significantly negative correlation with CELSR3 in MPCa. Besides, miRNA-221-3p expression was downregulated in MPCa than in LPCa (SMD = -1.04), and miRNA-221-3p was moderately capable of distinguishing MPCa from LPCa. Conclusions: CELSR3 seems to play a pivotal role in MPCa by affecting the focal adhesion pathway and/or being targeted by miRNA-221-3p.

Down-Regulation of Activating Transcription Factor 3 (ATF3) in Hepatoblastoma and Its Relationship with Ferroptosis.

PURPOSE: The molecular mechanisms and signal pathways of ferroptosis in hepatoblastoma (HB) have not yet been clarified. In previous studies, activating transcription factor 3 (ATF3) was reported to be correlated with several tumors, but the clinical significance of ATF3 has never been determined. Herein, we investigated the clinicopathological value and mechanisms of ATF3 in regulating ferroptosis in HB. METHODS: The mRNA microarray and RNA-sequencing data of 402 samples from our hospital and public databases were used to estimate ATF3 expression and assess its clinical role in HB. The standard mean difference (SMD) and summary receiver operating characteristic curves were utilized to judge the discrimination ability of ATF3 between HB and non-HB liver tissues. We examined the expression variation of ATF3 in HB cells after the treatment with erastin. We also predicted the target genes of ATF3 as a transcriptional factor from public Chromatin Immunoprecipitation-sequencing data and selected the ferroptosis-related genes for a signaling pathway analysis. RESULTS: In ten series, the pooled SMD for ATF3 was -0.91, demonstrating that ATF3 expression was predominantly lower in HB than in non-HB liver tissues. ATF3 down-regulation showed moderate potential to distinguish HB from non-HB liver tissues (area under curves = 0.83, 95% confidence interval = 0.79-0.86). Altogether, 4855 putative targets of ATF3 as a transcriptional factor were collected, among which, 60 genes were ferroptosis-related. CONCLUSION: The down-regulated ATF3 expression may play a vital role in the occurrence of HB possible partially by regulating ferroptosis.