Recent studies have proposed that pyruvate dehydrogenase E1 component subunit alpha (PDHA1), a cuproptosis-key gene, is crucial to the glucose metabolism reprogram of tumor cells. However, the functional roles and regulated mechanisms of PDHA1 in multiple cancers are largely unknown. The Cancer Genome Atlas (TCGA), GEPIA2, and cBioPortal databases were utilized to elucidate the function of PDHA1 in 33 tumor types. We found that PDHA1 was aberrantly expressed in most cancer types. Lung adenocarcinoma (LUAD) patients with high PDHA1 levels were significantly correlated with poor prognosis of overall survival (OS) and first progression (FP). Kidney renal clear cell carcinoma (KIRC) patients with low PDHA1 levels displayed poor OS and disease-free survival (DFS). However, for stomach adenocarcinoma (STAD), the downregulated PDHA1 expression predicted a good prognosis in patients. Moreover, we evaluated the mutation diversity of PDHA1 in cancers and their association with prognosis. We also analyzed the protein phosphorylation and DNA methylation of PDHA1 in various tumors. The PDHA1 expression was negatively correlated with tumor-infiltrating immune cells, such as myeloid dendritic cells (DCs), B cells, and T cells in pan-cancers. Mechanically, we used single-cell sequencing to discover that the PDHA1 expression had a close link with several cancer-associated signaling pathways, such as DNA damage, cell invasion, and angiogenesis. At last, we conducted a co-expressed enrichment analysis and showed that aberrantly expressed PDHA1 participated in the regulation of mitochondrial signaling pathways, including oxidative phosphorylation, cellular respiration, and electron transfer activity. In summary, PDHA1 could be a prognostic and immune-associated biomarker in multiple cancers.

Cuproptosis is a new form of copper-dependent programmed cell death commonly occurring within the body. There is emerging evidence indicating that cuproptosis has a significant regulatory function in the onset and progression of cancer. However, it is still unclear how cuproptosis regulates cancer and whether other genes are involved in the regulation. Using the TCGA-COAD dataset of 512 samples, we found that seven of ten cuproptosis markers showed prognostic value in colorectal cancer (CRC) using Kaplan–Meier survival analysis. Furthermore, 31 prognostic cuproptosis-related genes were identified using weighted gene co-expression network analysis and univariate Cox analysis. Subsequently, we constructed a 7-PCRG signature using least absolute shrinkage and selection operator (LASSO)–Cox regression analysis. The risk score predicting survival in patients with CRC was evaluated. Two risk groups were classified based on their risk scores. The two groups revealed a significant difference in immune cells, such as B and T cells. Furthermore, we identified differences in many immune functions and checkpoints, including CD276 and CD28. In vitro experiments showed that a hub cuproptosis-related gene, TIGD1, could significantly regulate cuproptosis in CRC after exposure to elesclomol. This study validated that cuproptosis was closely related to the progression of CRC. Seven new cuproptosis-related genes were identified, and the function of TIGD1 in cuproptosis was preliminarily understood. Since a certain concentration of copper in CRC cells is important, cuproptosis may provide a new target for cancer therapy. This study may provide novel insights into the treatment of CRC.

Breast cancer (BRCA) is one of the most common cancers in women. Copper (Cu) is an essential trace element implicated in many physiological processes and human diseases, including BRCA. In this study, we performed bioinformatics analysis and experiments to determine differentially expressed copper homeostasis-associated genes in BRCA. Based on two Gene Expression Omnibus (GEO) datasets, the copper homeostasis-associated gene, prion protein (PRNP), a highly conserved ubiquitous glycoprotein, was significantly down-regulated in BRCA compared to normal tissues. Moreover, PRNP expression predicted a better prognosis in BRCA patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that PRNP was potentially linked with several cancer-associated signaling pathways, including regulation of inflammatory response and oxidative phosphorylation. To validate the biological functions of PRNP, we overexpressed PRNP in BRCA cell lines, MDA-MB-231 and BT-549. CCK8 assay showed that PRNP overexpression significantly increased the sensitivity of gefitinib in BRCA cells. Overexpression of PRNP resulted in increased reactive oxygen species (ROS) production upon gefitinib treatment and ferroptosis selective inhibitor, ferrostatin-1 attenuated the enhanced ROS production effect of PRNP in BRCA cells. PRNP expression was positively correlated with macrophages, Th1 cells, neutrophils, and B cells, while negatively correlated with NK CD56 bright cells and Th17 cells in BRCA. Single-cell analysis showed that PRNP was highly expressed in M1 phenotype macrophages, essential tumor-suppressing cells in the tumor stroma. Therefore, our findings suggest that PRNP may participate in ROS-mediated ferroptosis and is a potential novel therapeutic target of chemotherapy and immunotherapy in BRCA.

Recent studies have suggested that ferroptosis, a form of iron-dependent regulated cell death, might play essential roles in tumor initiation and progression. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a ferrireductase involved in the regulation of intracellular iron homeostasis. However, the clinical significance and biological function of STEAP3 in human cancers remain poorly understood. Through a comprehensive bioinformatics analysis, we found that STEAP3 mRNA and protein expression were up-regulated in GBM, LUAD, and UCEC, and down-regulated in LIHC. Survival analysis indicated that STEAP3 had prognostic significance only in glioma. Multivariate Cox regression analysis revealed that high STEPA3 expression was correlated with poor prognosis. STEAP3 expression was significantly negatively correlated with promoter methylation level, and patients with lower STEAP3 methylation level had worse prognosis than those with higher STEAP3 methylation level. Single-cell functional state atlas showed that STEAP3 regulated epithelial-to-mesenchymal transition (EMT) in GBM. Furthermore, the results of wound healing and transwell invasion assays demonstrated that knocking down STEAP3 inhibited the migration and invasion of T98G and U251 cells. Functional enrichment analysis suggested that genes co-expressed with STEAP3 mainly participated in inflammation and immune-related pathways. Immunological analysis revealed that STEAP3 expression was significantly correlated with immune infiltration cells, including macrophages and neutrophils, especially the M2 macrophages. Individuals with low STEAP3 expression were more likely to respond to immunotherapy than those with high STEAP3 expression. These results suggest that STEAP3 promotes glioma progression and highlight its pivotal role in regulating immune microenvironment.

Background: It is critical to understand the mechanisms of human cancers in order to develop the effective anti-cancer therapeutic strategies. Recent studies indicated that primase polymerase (PRIMPOL) is strongly associated with the development of human cancers. Nevertheless, a systematic pan-cancer analysis of PRIMPOL remains to be further clarified. Method: Comprehensive multi-omics bioinformatics algorithms, such as TIMER2.0, GEPIA2.0 and cBioPortal, were utilized to evaluate the biological roles of PRIMPOL in pan-cancer, including the expression profiles, genomic alterations, prognostic values and immune regulation. Results: PRIMPOL was upregulated in glioblastoma multiforme and kidney renal clear cell carcinoma. The brain lower grade glioma patients with enhanced PRIMPOL expression displayed poor prognostic values. We also demonstrated the PRIMPOL's immunomodulating effects on pan-cancer as well as its genomic changes and methylation levels. The aberrant expression of PRIMPOL was linked to various cancer-associated pathways, including DNA damage response, DNA repair, and angiogenesis, according to single-cell sequencing and function enrichment. Conclusions: This pan-cancer analysis offers a thorough review of the functional roles of PRIMPOL in human cancers, suggesting PRIMPOL as a potentially important biomarker for the progression and immunotherapy of various cancers.

Breast cancer (BRCA), the most frequent malignancy in women, is a highly heterogeneous disease. Chemoresistant is the main factor for the BRCA treatment failure. However, the mechanism underlying chemoresistant is still unclear. In this study, we performed comprehensive bioinformatics to verify differentially expressed cell death genes between BRCA and normal tissues. CFLAR was down-regulated in BRCA patients and high expression level of CFLAR exhibited improved prognosis in BRCA patients. CFLAR played a key role in regulating tumor growth. However, the role of CFLAR in different BRCA subtype and its influence in drug resistance and immune therapy need further clarification. CFLAR was decreased in Ki67 positive patients and increased in ER and PR positive patients. CFLAR was significantly down-regulated in Luminal and TNBC than normal breast tissue. CFALR is higher in drug respond patients than drug non-respond patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that aberrantly expressed CFLAR was potentially linked with oxidative phosphorylation, T cell receptor signaling pathway, NADH dehydrogenase (ubiquinone) activity, NADH dehydrogenase (quinone) activity, oxidoreductase activity and oxidoreductase-driven active transmembrane transporter activity. Through cell colony formation experiment, overexpression of CFLAR could inhibit reactive oxygen species (ROS) upon 5-FU treatment and promote 5-FU sensitivity in BT-549 and MDA-MB-231cells. In addition, we verified that CFLAR expression was positively correlated with Tcm, T helper cells, Tem, T cells, B cells NK CD56 bright cells and Th2 cells, especially CD8 + T cells. CFALR was higher in CAR-T response patients, anti-PD-L1 response patients and anti-PD1 patients. In summary, CFLAR could regulated ROS homeostasis and ameliorates 5-FU sensitivity of breast cancer cell. CFLAR may be a novel therapeutic target in BRCA.