Disulfiram enhances the antitumor activity of cisplatin by inhibiting the Fanconi anemia repair pathway. / åŒç¡«ä»‘é€šè¿‡æŠ‘åˆ¶èŒƒå¯å°¼è´«è¡€ä¿®å¤é€”å¾„å¢žåŠ é¡ºé“‚çš„æŠ—è‚¿ç˜¤æ´»æ€§.

A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.

Identification and Validation of Two Heterogeneous Molecular Subtypes and a Prognosis Predictive Model for Hepatocellular Carcinoma Based on Pyroptosis.

Hepatocellular carcinoma (HCC) is a worldwide malignant cancer with high incidence and mortality. Considering the high heterogeneity of HCC, clarifying molecular characteristics associated with HCC development could help improve patients' outcomes. Pyroptosis is a novel form of cell death and is noted to be implicated in HCC pathogenesis whereas its molecular feature in HCC is unclear. Thus, we intended to clarify the molecular characteristic as well as the clinical significance of pyroptosis for HCC. A systematic bioinformatics analysis was conducted among 40 pyroptosis-related genes based on The Cancer Genome Atlas, the International Cancer Genome Consortium, and the Gene Expression Omnibus databases. A total of 12 HCC-associated pyroptosis-related genes (HPRGs) were identified to be overexpressed in HCC tissues and significantly connected to patients' poor survival. Through consensus clustering based on the HPRGs' expression, we found patients could be stratified into two distinctive pyroptosis subtypes, PyLow and PyHigh. The PyHigh group owned a notable lower survival rate and a higher high-grade proportion compared with the PyLow subtype. Besides, patients' sensitivities to chemotherapeutic drugs also presented distinctive differences between the two subtypes. Indicated by pathway enrichment analysis and immune characteristic difference analysis, the distinctions between the pyroptosis subtypes may be related to tumor immunity. Further, a five-gene risk model composed of BAK1, CHMP4A, CHMP4B, DHX9, and GSDME was established. Subsequent analyses demonstrated that the model could credibly classify patients as low or high risk and was an independent prognostic indicator for HCC. Abnormal expressions of the five genes were validated by biological experiments and new bioinformatics analysis. In conclusion, this study recognized and verified two heterogeneous pyroptosis subtypes and a predictable prognosis model for HCC. Our work may help facilitate the clinical management and treatment of HCC and understand the functions of pyroptosis in oncology.

Upregulation of Centromere Proteins as Potential Biomarkers for Esophageal Squamous Cell Carcinoma Diagnosis and Prognosis.

Esophageal squamous cell carcinoma (ESCC) has a high incidence and low survival rate, necessitating the identification of novel specific biomarkers. Centromere-associated proteins (CENPs) have been reported to be biomarkers for many cancers, but their roles in ESCC have seldom been investigated. Here, the potential clinical roles of CENPs in ESCC patients were demonstrated by a systematic bioinformatics analysis. Most CENP-encoding genes were differentially expressed between tumor and normal tissues. CENPA, CENPE, CENPF, CENPI, CENPM, CENPN, CENPQ, and CENPR were upregulated universally in the three datasets. Survival analysis demonstrated that high expression of CENPE and CENPQ was positively correlated with the outcomes of ESCC patients. The CENPE-based forecast model was more accurate than the tumor-node-metastasis (TNM) staging-based model, which was classified as stage I/II vs. III/IV. More importantly, the forecast model based on the commonly upregulated CENPs exhibited a much higher area under the curve (AUC) value (0.855) than the currently known TTL, ZNF750, AC016205.1, and BOLA3 biomarkers. The nomogram model integrating the CENPs, TNM stage, and sex was highly accurate in the prognosis of ESCC patients (AUC = 0.906). Besides, gene set enrichment analysis (GSEA) demonstrated that CENPE expression is significantly correlated with cell cycle, G2/M checkpoint, mitotic spindle, p53, etc. Finally, in validation experiments, we also found that CENPE and CENPQ were significantly overexpressed in esophageal cancer cells. Taken together, these results clearly suggest that CENPs are clinically promising diagnostic and prognostic biomarkers for ESCC patients.

Identification of CHRNB4 as a Diagnostic/Prognostic Indicator and Therapeutic Target in Human Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors and there is a lack of biomarkers for ESCC diagnosis and prognosis. Family subunits of cholinergic nicotinic receptor genes (CHRNs) are involved in smoking behavior and tumor cell proliferation. Previous researches have shown similar molecular features and pathogenic mechanisms among ESCC, head and neck squamous cell carcinoma (HNSC), and lung squamous cell carcinoma (LUSC). Using edgeR, three mutual differentially expressed genes of CHRNs were found to be significantly upregulated at the mRNA level in ESCC, LUSC, and HNSC compared to matched normal tissues. Kaplan-Meier survival analysis showed that high expression of CHRNB4 was associated with unfavorable prognosis in ESCC and HNSC. The specific expression analysis revealed that CHRNB4 is highly expressed selectively in squamous cell carcinomas compared to adenocarcinoma. Cox proportional hazards regression analysis was performed to find that just the single gene CHRNB4 has enough independent prognostic ability, with the area under curve surpassing the tumor-node-metastasis (TNM) staging-based model, the most commonly used model in clinical application in ESCC. In addition, an effective prognostic nomogram was established combining the TNM stage, gender of patients, and expression of CHRNB4 for ESCC patients, revealing an excellent prognostic ability when compared to the model of CHRNB4 alone or TNM. Gene Set Enrichment Analysis results suggested that the expression of CHRNB4 was associated with cancer-related pathways, such as the mTOR pathway. Cell Counting Kit-8, cloning formation assay, and western blot proved that CHRNB4 knockdown can inhibit the proliferation of ESCC cells via the Akt/mTOR and ERK1/2/mTOR pathways, which might facilitate the prolonged survival of patients. Furthermore, we conducted structure-based molecular docking, and potential modulators against CHRNB4 were screened from FDA approved drugs. These findings suggested that CHRNB4 specifically expressed in SCCs, and may serve as a promising biomarker for diagnosis and prognosis prediction, and it can even become a therapeutic target of ESCC patients.

Construction of a CXC Chemokine-Based Prediction Model for the Prognosis of Colon Cancer.

Colon cancer is the third most common cancer, with a high incidence and mortality. Construction of a specific and sensitive prediction model for prognosis is urgently needed. In this study, profiles of patients with colon cancer with clinical and gene expression data were downloaded from Gene Expression Omnibus and The Cancer Genome Atlas (TCGA). CXC chemokines in patients with colon cancer were investigated by differential expression gene analysis, overall survival analysis, receiver operating characteristic analysis, gene set enrichment analysis (GSEA), and weighted gene coexpression network analysis. CXCL1, CXCL2, CXCL3, and CXCL11 were upregulated in patients with colon cancer and significantly correlated with prognosis. The area under curve (AUC) of the multigene forecast model of CXCL1, CXCL11, CXCL2, and CXCL3 was 0.705 in the GSE41258 dataset and 0.624 in TCGA. The prediction model was constructed using the risk score of the multigene model and three clinicopathological risk factors and exhibited 92.6% and 91.8% accuracy in predicting 3-year and 5-year overall survival of patients with colon cancer, respectively. In addition, by GSEA, expression of CXCL1, CXCL11, CXCL2, and CXCL3 was correlated with several signaling pathways, including NOD-like receptor, oxidative phosphorylation, mTORC1, interferon-gamma response, and IL6/JAK/STAT3 pathways. Patients with colon cancer will benefit from this prediction model for prognosis, and this will pave the way to improve the survival rate and optimize treatment for colon cancer.