Ling Liu

Introduction: Esophageal squamous cell carcinoma (ESCA) is one of the most common cancers worldwide. PANoptosis is an inflammatory programmed cell death pathway event regulated by the PANoptosome complex. Currently, there is limited research on the PANoptosis-related genes (PORGs) in ESCA. We aim to explore the prognostic biomarkers of PANoptosis in ESCA and their underlying mechanisms through comprehensive bioinformatics analysis. Methods: In this study, we analyzed transcriptome and single-cell RNA sequencing (scRNA-seq) data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were used to identify PANoptosis-related differentially expressed genes (POR-DEGs) in esophageal cancer. Hub genes were screened by univariate and multivariate Cox regression combined with machine learning models to construct diagnostic and prognostic models. The potential mechanisms of hub genes in esophageal cancer were preliminarily explored through gene immune infiltration and functional enrichment analysis. The differences and driving factors between high- and low-risk subgroups, as well as the regulation of PANoptosis by hub genes related to macrophages, were further revealed by immune assessment, drug sensitivity analysis, single-cell analysis, and molecular docking. Finally, the accuracy of model genes was verified by immunohistochemistry in clinical samples. Results: Firstly, 74 PANoptosis-related differentially expressed genes (POR-DEGs) were identified for further analysis. Among the 74 genes, CCT6A, GMNN, and HSPB6 were identified as hub genes, and the constructed diagnostic and prognostic models were valuable. The high-risk subgroup showed poor prognosis, immune exhaustion, significant activation of pDC-LILRA4 cells, poor response to immunotherapy, and moderate sensitivity to chemotherapy. Further exploration of the immune regulatory mechanism of prognostic biomarkers revealed that the three hub genes, CCT6A, GMNN, and HSPB6, were closely related to the ESCA immune microenvironment. The CCT6A targeted by the traditional Chinese medicine component quercetin may inhibit PANoptosis by promoting the differentiation of Mono-CD14 cells into TAM-SPP1 macrophages. Discussion: We constructed prognostic and diagnostic models using PANoptosis-related prognostic biomarkers, analyzed the differences and treatments between high-risk and low-risk groups, and revealed a new mechanism by which CCT6A may inhibit PANoptosis by promoting TAM-SPP1 differentiation, providing new targets and biomarkers for ESCA treatment.

Background Esophageal cancer (ESCA) is a common malignant tumor of the digestive tract, and its poor prognosis is mainly attributed to the occurrence of invasion and metastasis. Z-DNA binding protein 1 (ZBP1), as a mRNA regulatory factor, plays an important role in the occurrence and development of various tumors. However, the role of ZBP1 in ESCA is not yet understood. Aims This study aims to explore the expression of ZBP1 in ESCA and its role in the development of ESCA. Methods Using bioinformatics analysis and immunohistochemistry staining, we detected the expression of ZBP1 in ESCA and normal tissues. The potential mechanism of ZBP1 in ESCA was analyzed from the aspects of genetic mutations, protein interaction networks, and pathway enrichment. We performed functional experiments in vitro to elucidate the effect of ZBP1 on ESCA cells. Results ZBP1 was found to be significantly upregulated in ESCA compared to adjacent noncancerous tissues, and its expression is closely related to gender, age, and lymph node metastasis. In ESCA, the genetic variation rate of ZBP1 is 8%, and its expression is positively correlated with immune cell infiltration. The ZBP1 co-expressed gene is mainly involved in processes such as lymph node proliferation and intercellular adhesion. In vitro experiments have confirmed that downregulation of ZBP1 significantly inhibited the proliferation, migration, and invasion of ESCA cells. Conclusion This research proves that downregulation of ZBP1 can inhibit the progression of ESCA. This finding indicates that ZBP1 may be a novel biomarker to improve the diagnosis and treatment of ESCA. Graphical Abstract

Breast cancer arises from the malignant transformation of mammary epithelial cells under the influence of various carcinogenic factors, leading to a gradual increase in its prevalence. This disease has become the leading cause of mortality among female malignancies, posing a significant threat to the health of women. The timely identification of breast cancer remains challenging, often resulting in diagnosis at the advanced stages of the disease. Conventional therapeutic approaches, such as surgical excision, chemotherapy and radiotherapy, exhibit limited efficacy in controlling the progression and metastasis of the disease. Regulated cell death (RCD), a process essential for physiological tissue cell renewal, occurs within the body independently of external influences. In the context of cancer, research on RCD primarily focuses on cuproptosis, ferroptosis and pyroptosis. Mounting evidence suggests a marked association between these specific forms of RCD, and the onset and progression of breast cancer. For example, a cuproptosis vector can effectively bind copper ions to induce cuproptosis in breast cancer cells, thereby hindering their proliferation. Additionally, the expression of ferroptosis‑related genes can enhance the sensitivity of breast cancer cells to chemotherapy. Likewise, pyroptosis‑related proteins not only participate in pyroptosis, but also regulate the tumor microenvironment, ultimately leading to the death of breast cancer cells. The present review discusses the unique regulatory mechanisms of cuproptosis, ferroptosis and pyroptosis in breast cancer, and the mechanisms through which they are affected by conventional cancer drugs. Furthermore, it provides a comprehensive overview of the significance of these forms of RCD in modulating the efficacy of chemotherapy and highlights their shared characteristics. This knowledge may provide novel avenues for both clinical interventions and fundamental research in the context of breast cancer.

Purpose:To investigate the regulatory effect of Survivin on autolysosome formation-associated proteins in esophageal cancer cell (ESCC) line Eca109.Methods: An autophagy induction model was constructed using rapamycin (RAPA), an autophagy inhibitor. The Survivin overexpression vector, shRNA vector, and Survivin inhibitor YM155 were used to interfere with the autophagy model. Laser copolymer microscopy technology was utilized to observe the changes in autophagosomes and their progression, while western blotting was used to detect the the level of lysosome formation-related proteins after autophagy. Besides, immunofluorescence staining was used to determine the pH of lysosomes and the distribution of cathepsin-D in cells.Results: (1)Eca109 cells transfected with MRFP-EGFP-LC3 vector by RAPA showed a significant increase in green fluorescence, indicating an increase in autophagosomes. Results from western blotting indicated a rise in protein expression levels of LC3-I and LC3-II, an increase in the ratio of LC3-II/LC3-I, and a decrease in the expression of p62 levels, indicating enhanced autophagy. (2)In the autophagy model of Eca109 cells, after Survivin overexpression, LC3 expression increased, ATG5 expression decreased(PPPP<0.05).(4)Decreased Survivin can reduce p62 expression and increase autophagy.(5)Survivin overexpression increased the number of intracellular lysosomes and was involved in the regulation of lysosomal pH changes. Besides, inhibition of Survivin expression resulted in the extravasation of cathepsin-D, which was dispersive and affected the permeability of lysosomes.Conclusion: Survivin expression was directly related to the expression of the autophagy-associated protein LC3 and P62.Survivin is associated with the autophagic process in cancer cells at specific periods, which indicates that Survivin is involved in both early autophagy formation and the later stages of autolysosomal function implementation.

The present study analyzed the expression of the histone deacetylase (HDAC) 1, 2 and 3 in primary esophageal squamous cell carcinoma (ESCC) samples and how their levels correlate with clinicopathological parameters. ESCC patients (n=88) in the present study had received no previous treatment before undergoing surgical excision. The mRNA expression of HDAC1, ‑2 and ‑3 were detected by semi‑quantified PCR in ESCC samples and distal normal samples. The relationship of HDAC1, ‑2 and ‑3 expression with clinicopathological parameters was analyzed by χ2 test. The correlation among these HDACs was analyzed by Pearson's correlation test. Compared with distal normal tissues, ESCC samples had higher expression of HDAC1, but not HDAC2 or HDAC3 (P0.05). For the Kazak and Han ethnicities, HDAC1 expression was present in male patients, patients with well/moderate differentiated ESCC and T3 and T4 ESCC (P<0.01). HDAC1 in patients aged <60 was associated with ethnicity (P<0.05). HDAC2 expression was different in positive LN metastasis, well/moderate differentiation and T3 and T4 ESCC (P<0.01). HDAC3 expression in male patients, patients with negative LN metastasis and well/moderate differentiation ESCC was associated with ethnicity (P<0.05). Additionally, the expression levels of HDAC1, ‑2 and ‑3 did not correlate with each other. Thus, HDAC1 expression may be used as a risk factor for ESCC and HDAC2 levels may be used to predict invasion depth. The expression of HDAC1, ‑2 and ‑3 has ethnic differences.

Background: Essential hypertension (EH) is a complex disease as a consequence of interaction between environmental factors and genetic background, but the pathogenesis of EH remains elusive. The emerging tools of network medicine offer a platform to explore a complex disease at system level. In this study, we aimed to identify the key proteins and the biological regulatory pathways involving in EH and further to explore the molecular connectivities between these pathways by the topological analysis of the Protein-protein interaction (PPI) network. Result: The extended network including one giant network consisted of 535 nodes connected via 2572 edges and two separated small networks. 27 proteins with high BC and 28 proteins with large degree have been identified. NOS3 with highest BC and Closeness centrality located in the centre of the network. The backbone network derived from high BC proteins presents a clear and visual overview which shows all important regulatory pathways for blood pressure (BP) and the crosstalk between them. Finally, the robustness of NOS3 as central protein and accuracy of backbone were validated by 287 test networks. Conclusion: Our finding suggests that blood pressure variation is orchestrated by an integrated PPI network centered on NOS3.