Pan-cancer analysis of necroptosis-related gene signature for the identification of prognosis and immune significance.

Necroptosis is a novel programmed cell death mode independent on caspase. A number of studies have revealed that the induction of necroptosis could act as an alternative therapeutic strategy for drug-resistant tumors as well as affect tumor immune microenvironment. Gene expression profiles and clinical data were downloaded from XENA-UCSC (including The Cancer Genome Atlas and Genotype-Tissue Expression), Gene Expression Omnibus, International Cancer Genome Consortium and Chinese Glioma Genome Atlas. We used non-negative matrix factorization method to conduct tumor classification. The least absolute shrinkage and selection operator regression was applied to establish risk models, whose prognostic effectiveness was examined in both training and testing sets with Kaplan-Meier analysis, time-dependent receiver operating characteristic curves as well as uni- and multi-variate survival analysis. Principal Component Analysis, t-distributed Stochastic Neighbor Embedding and Uniform Manifold Approximation and Projection were conducted to check the risk group distribution. Gene Set Enrichment Analyses, immune infiltration analysis based on CIBERSORT, EPIC, MCPcounter, ssGSEA and ESTIMATE, gene mutation and drug sensitivity between the risk groups were also taken into consideration. There were eight types of cancer with at least ten differentially expressed necroptosis-related genes which could influence patients' prognosis, namely, adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pancreatic adenocarcinoma (PAAD), liver hepatocellular carcinoma (LIHC), skin cutaneous melanoma (SKCM) and thymoma (THYM). Patients could be divided into different clusters with distinct overall survival in all cancers above except for LIHC. The risk models could efficiently predict prognosis of ACC, LAML, LGG, LIHC, SKCM and THYM patients. LGG patients from high-risk group had a higher infiltration level of M2 macrophages and cancer-associated fibroblasts. There were more CD8+ T cells, Th1 cells and M1 macrophages in low-risk SKCM patients' tumor microenvironment. Gene mutation status and drug sensitivity are also different between low- and high-risk groups in the six cancers. Necroptosis-related genes can predict clinical outcomes of ACC, LAML, LGG, LIHC, SKCM and THYM patients and help to distinguish immune infiltration status for LGG and SKCM.

Ma J ，Jin Y ，Gong B ，Li L ，Zhao Q ... -  《-》

APOBEC3C is a novel target for the immune treatment of lower-grade gliomas.

Zhao S ，Li Y ，Xu J ，Shen L ... -  《-》

Identification of SHCBP1 as a potential biomarker involving diagnosis, prognosis, and tumor immune microenvironment across multiple cancers.

Shc SH2-domain binding protein 1 (SHCBP1), a protein specific binding to SH2 domain of Src homolog and collagen homolog (Shc), takes part in the regulation of various signal transduction pathways, which has been reported to be associated with tumorigenesis and progression. However, the pathological mechanisms are not completely investigated. Thus, this study aimed to comprehensively elucidate the potential functions of SHCBP1 in multiple cancer types. The comprehensive analyses for SHCBP1 in various tumors, including gene expression, diagnosis, prognosis, immune-related features, genetic alteration, and function enrichment, were conducted based on multiple databases and analysis tools. SHCBP1 was upregulated in most types of cancers. The results of qRT-PCR had confirmed that SHCBP1 mRNA was significantly upregulated in lung adenocarcinoma (LUAD) and liver hepatocellular carcinoma (LIHC) cell lines. Based on the receiver operating characteristic (ROC) and survival analysis, SHCBP1 was considered as a potential diagnostic and prognostic biomarker. Furthermore, SHCBP1 expression was linked with tumor immunity and immunosuppressive microenvironment according to the correlation analysis of SHCBP1 expression with immune cells infiltration, immune checkpoint genes, and immune-related genes (MHC genes, chemokines, and chemokines receptors). Moreover, SHCBP1 expression correlated with tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens. The feature of SHCBP1 mutational landscape in pan-cancer was identified. Finally, we focused on investigating the clinical significance and the potential biological role of SHCBP1 in LUAD. Our study comprehensively uncovered that SHCBP1 could be identified as an immune-related biomarker for cancer diagnosis and prognosis, and a potential therapeutic target for tumor immunotherapy.

Wang N ，Zhu L ，Wang L ，Shen Z ，Huang X ... -  《Computational and Structural Biotechnology Journal》

Identifies microtubule-binding protein CSPP1 as a novel cancer biomarker associated with ferroptosis and tumor microenvironment.

Centrosome and spindle pole-associated protein (CSPP1) is a centrosome and microtubule-binding protein that plays a role in cell cycle-dependent cytoskeleton organization and cilia formation. Previous studies have suggested that CSPP1 plays a role in tumorigenesis; however, no pan-cancer analysis has been performed. This study systematically investigates the expression of CSPP1 and its potential clinical outcomes associated with diagnosis, prognosis, and therapy. CSPP1 is widely present in tissues and cells and its aberrant expression serves as a diagnostic biomarker for cancer. CSPP1 dysregulation is driven by multi-dimensional mechanisms involving genetic alterations, DNA methylation, and miRNAs. Phosphorylation of CSPP1 at specific sites may play a role in tumorigenesis. In addition, CSPP1 correlates with clinical features and outcomes in multiple cancers. Take brain low-grade gliomas (LGG) with a poor prognosis as an example, functional enrichment analysis implies that CSPP1 may play a role in ferroptosis and tumor microenvironment (TME), including regulating epithelial-mesenchymal transition, stromal response, and immune response. Further analysis confirms that CSPP1 dysregulates ferroptosis in LGG and other cancers, making it possible for ferroptosis-based drugs to be used in the treatment of these cancers. Importantly, CSPP1-associated tumors are infiltrated in different TMEs, rendering immune checkpoint blockade therapy beneficial for these cancer patients. Our study is the first to demonstrate that CSPP1 is a potential diagnostic and prognostic biomarker associated with ferroptosis and TME, providing a new target for drug therapy and immunotherapy in specific cancers.

Wang W ，Zhang J ，Wang Y ，Xu Y ，Zhang S ... -  《Computational and Structural Biotechnology Journal》

The molecular feature of macrophages in tumor immune microenvironment of glioma patients.

Gliomas are one of the most common types of primary tumors in central nervous system. Previous studies have found that macrophages actively participate in tumor growth. Weighted gene co-expression network analysis was used to identify meaningful macrophage-related gene genes for clustering. Pamr, SVM, and neural network were applied for validating clustering results. Somatic mutation and methylation were used for defining the features of identified clusters. Differentially expressed genes (DEGs) between the stratified groups after performing elastic regression and principal component analyses were used for the construction of MScores. The expression of macrophage-specific genes were evaluated in tumor microenvironment based on single cell sequencing analysis. A total of 2365 samples from 15 glioma datasets and 5842 pan-cancer samples were used for external validation of MScore. Macrophages were identified to be negatively associated with the survival of glioma patients. Twenty-six macrophage-specific DEGs obtained by elastic regression and PCA were highly expressed in macrophages at single-cell level. The prognostic value of MScores in glioma was validated by the active proinflammatory and metabolic profile of infiltrating microenvironment and response to immunotherapies of samples with this signature. MScores managed to stratify patient survival probabilities in 15 external glioma datasets and pan-cancer datasets, which predicted worse survival outcome. Sequencing data and immunohistochemistry of Xiangya glioma cohort confirmed the prognostic value of MScores. A prognostic model based on MScores demonstrated high accuracy rate. Our findings strongly support a modulatory role of macrophages, especially M2 macrophages in glioma progression and warrants further experimental studies.

Zhang H ，Luo YB ，Wu W ，Zhang L ，Wang Z ，Dai Z ，Feng S ，Cao H ，Cheng Q ，Liu Z ... -  《Computational and Structural Biotechnology Journal》