The phosphatidylinositol-3-kinase catalytic subunit α (PIK3CA) gene is mutated in numerous human cancers. This mutation promotes the proliferation of tumor cells; however, the underlying mechanism is still not clear. In the present study, it was revealed that the PIK3CA mutation in colorectal cancer (CRC) HCT116 (MUT) rendered the cells more dependent on glutamine by regulating the glutamic-pyruvate transaminase 2 (GPT2).

Background. Pyroptosis is closely related to the programmed death of cancer cells as well as the tumor immune microenvironment (TIME) via the host-tumor crosstalk. However, the role of pyroptosis-related genes as prognosis and TIME-related biomarkers in skin cutaneous melanoma (SKCM) patients remains unknown. Methods. We evaluated the expression profiles, copy number variations, and somatic mutations (CNVs) of 27 genes obtained from MSigDB database regulating pyroptosis among TCGA-SKCM patients. Thereafter, we conducted single-sample gene set enrichment analysis (ssGSEA) for evaluating pyroptosis-associated expression patterns among cases and for exploring the associations with clinicopathological factors and prognostic outcome. In addition, a prognostic pyroptosis-related signature (PPRS) model was constructed by performing Cox regression, weighted gene coexpression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO) analysis to score SKCM patients. On the other hand, we plotted the ROC and survival curves for model evaluation and verified the robustness of the model through external test sets (GSE22153, GSE54467, and GSE65904). Meanwhile, we examined the relations of clinical characteristics, oncogene mutations, biological processes (BPs), tumor stemness, immune infiltration degrees, immune checkpoints (ICs), and treatment response with PPRS via multiple methods, including immunophenoscore (IPS) analysis, gene set variation analysis (GSVA), ESTIMATE, and CIBERSORT. Finally, we constructed a nomogram incorporating PPRS and clinical characteristics to improve risk evaluation of SKCM. Results. Many pyroptosis-regulated genes showed abnormal expression within SKCM. TP53, TP63, IL1B, IL18, IRF2, CASP5, CHMP4C, CHMP7, CASP1, and GSDME were detected with somatic mutations, among which, a majority displayed CNVs at high frequencies. Pyroptosis-associated profiles established based on pyroptosis-regulated genes showed markedly negative relation to low stage and superior prognostic outcome. Blue module was found to be highly positively correlated with pyroptosis. Later, this study established PPRS based on the expression of 8 PAGs (namely, GBP2, HPDL, FCGR2A, IFITM1, HAPLN3, CCL8, TRIM34, and GRIPAP1), which was highly associated with OS, oncogene mutations, tumor stemness, immune infiltration degrees, IC levels, treatment responses, and multiple biological processes (including cell cycle and immunoinflammatory response) in training and test set samples. Conclusions. Based on our observations, analyzing modification patterns associated with pyroptosis among diverse cancer samples via PPRS is important, which can provide more insights into TIME infiltration features and facilitate immunotherapeutic development as well as prognosis prediction.

The high-mobility group box 1 (HMGB1) protein is a highly conserved nuclear protein, that plays an important role in tumorigenesis and development of cancer cells; however, its exact mechanism remains to be elucidated. In this study, we found that HMGB1 endogenously expressed in Lewis lung cancer cells can promote proliferation of these cells. However, when Lewis cell lysates were introduced to immune cells, HMGB1 in tumor cell lysates (TCL) was found to have immunosuppressive effects, such as inducing apoptosis and inhibiting cytokine secretion. This inhibitory effect was found to be weakened after removing HMGB1 from TCL. Signal transduction pathway studies have shown that HMGB1 in TCL can inhibit the NF-кB signaling pathway in immune cells. It can also downregulate the expression of NF-кB, MMP-9, Bcl-2, and other cell-activating factors and simultaneously promote the expression of apoptosis-inducing factor Casp9. However, endogenous HMGB1 has the opposite effect on these signal transduction molecules in Lewis lung cancer cells. In summary, HMGB1 endogenously expressed in Lewis lung cancer cells can promote the proliferation of tumor cells, but the release of HMGB1 from necrotic and ruptured tumor cells induces immune cell apoptosis and functional inhibition. This enables HMGB1 to promote tumorigenesis while protecting cancer cells from attack by immune cells, thereby creating a microenvironment conducive to the growth of lung cancer cells. This induction of tumorigenesis is related to the activation of the NF-кB signaling pathway in tumor or immune cells in different ways.

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