Biological systems do not exist in isolation. Analogous to the intricate design of a spider web, the metabolic adaptations propagated by glioblastoma cells are interlaced, creating a "defense mechanism" that increases the likelihood of mutagenesis and proliferation, while mitigating stress-induced tumor cell death and immune evasion. Previous studies have observed the role of cardiolipin (CL) in the electron transport chain (ETC) function and several other intracellular signaling pathways. Our review provides a synopsis of the existing knowledge about CL in glioblastoma and its complex relationship with metabolic reprogramming at the subcellular level. Through a meticulous examination of CL defects due to its biogenesis and stress-induced modifications, we seek to elucidate the multifaceted connections between aberrant CL variants and the metabolic alterations that underlie glioblastoma progression. A comprehensive grasp of these mechanisms could provide future direction in designing chemotherapeutic agents that selectively target glioblastoma, are less harmful to normal cells, and therefore, may extend patient survival.

In this study, we sought to identify key molecular players in both thyroid cancer (TC) and Hashimoto's thyroiditis (HT) by analyzing differentially expressed genes (DEGs) and their potential as biomarkers. We utilized datasets from the Gene Expression Omnibus (GEO) database and identified CLTA, EDIL3, HAPLN1, and HIP1 as hub genes common to both TC and HT. These genes were significantly upregulated in TC cell lines compared to normal controls, with high diagnostic accuracy as indicated by Receiver Operating Characteristic (ROC) curve analysis. Further validation using the TCGA TC dataset revealed their significant upregulation in tumor tissues, particularly in advanced TC stages. Promoter methylation analysis indicated hypomethylation of these genes in TC, suggesting a role of methylation in their regulation. We also observed mutations and copy number variations (CNVs) in these hub genes, with CLTA and HIP1 showing significant amplifications, which may contribute to their overexpression in tumor samples. In addition, we conducted a meta-analysis to assess the impact of these genes on survival outcomes in TC patients, with results indicating that higher expression of HAPLN1 and HIP1 was associated with poor survival. Our study also highlighted the involvement of CLTA and EDIL3 in activating the Rap1 signaling pathway, crucial for cancer cell migration, proliferation, and invasion. These findings emphasize the potential of CLTA, EDIL3, HAPLN1, and HIP1 as diagnostic biomarkers and therapeutic targets for TC and HT.

Glioma, a prevalent malignant intracranial tumor, exhibits limited therapeutic efficacy due to its immunosuppressive microenvironment, leading to a poor prognosis for patients. ARHGDIB is implicated in the remodeling of the tumor microenvironment and plays a significant role in the pathogenesis of various tumors. However, its regulatory effect within the immune microenvironment of glioma remains unclear.

Xeroderma pigmentosum group D (XPD) has been reported to inhibit cell growth of hepatocellular carcinoma (HCC). This work attempted to reveal the underlying mechanism of XPD in HCC. In this study, XPD and miR-29a-3p were down-regulated, and MIAT and COL4A1 were up-regulated in tumor tissues of HCC patients. The same phenomena were also observed in HCC cell lines. XPD overexpression enhanced E-cadherin expression, reduced N-cadherin and Vimentin expression, and repressed the migration and invasion of HepG2 and Hep3B cells. MIAT or COL4A1 overexpression reversed the effect of XPD on the invasion, migration, and epithelial-mesenchymal transition (EMT) of HCC cells. MIAT overexpression-mediated promotion of malignant phenotypes of HCC cells was reversed by COL4A1 deficiency. In terms of mechanics, MIAT enhanced COL4A1 expression by sponging miR-29a-3p. XPD interacted with P53. XPD overexpression repressed MIAT expression, which was abrogated by P53 silencing. Thus, XPD recruited P53 to repress MIAT expression. In vivo, XPD up-regulation inhibited tumor growth and reduced the metastatic lesions in intrahepatic, lung, and kidney tissues of mice. In conclusion, this study demonstrated that XPD recruited P53 to regulate the MIAT/miR-29a-3p/COL4A1 axis, which contributed to inhibiting migration, invasion, EMT, and metastasis of HCC. Thus, XPD may be a valuable target for HCC treatment.

Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA (KrasG12D/+ Trp53R172H/+ Ad-Cre) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I-deficient tumor cells cocultured with T cells were more susceptible to T cell-mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I-knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. ST6GalNAc-I-deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I-mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.

Altered protein homeostasis through proteasomal degradation of ubiquitinated proteins is a hallmark of many cancers. Ubiquitination, coordinated by E1, E2, and E3 enzymes, involves up to 40 E2-conjugating enzymes in humans to specify substrates and ubiquitin linkages. In a screen for E2 dependencies in acute myeloid leukemia (AML), ubiquitin conjugating enzyme E2 N (UBE2N) emerged as the top candidate. To investigate UBE2N's role in AML, we characterized an enzymatically defective mouse model of UBE2N, revealing UBE2N's requirement in AML without an impact on normal hematopoiesis. Unlike other E2s, which mediate lysine-48 (K48) polyubiquitination and degradation of proteins, UBE2N primarily synthesizes K63-linked chains, stabilizing or altering protein function. Proteomic analyses and a whole-genome CRISPR-activation screen in pharmacologically and genetically UBE2N-inhibited AML cells unveiled a network of UBE2N-regulated proteins, many of which are implicated in cancer. UBE2N inhibition reduced their protein levels, leading to increased K48-linked ubiquitination and degradation through the immunoproteasome and revealing UBE2N activity is enriched in immunoproteasome-positive AML. Furthermore, an interactome screen identified tripartite motif-containing protein 21 (TRIM21) as the E3 ligase partnering with activated UBE2N in AML to modulate UBE2N-dependent proteostasis. In conclusion, UBE2N maintains proteostasis in AML by stabilizing target proteins through K63-linked ubiquitination and prevention of K48 ubiquitin-mediated degradation by the immunoproteasome. Thus, inhibition of UBE2N catalytic function suppresses leukemic cells through selective degradation of critical proteins in immunoproteasome-positive AML.

Alternative polyadenylation (APA) is a widespread post-transcriptional mechanism that diversifies gene expression by generating messenger RNA isoforms with varying 3' untranslated regions. Accurate identification and quantification of transcriptome-wide polyadenylation site (PAS) usage are essential for understanding APA-mediated gene regulation and its biological implications. In this review, we first review the landscape of computational tools developed to identify APA events from RNA sequencing (RNA-seq) data. We then benchmarked five PAS prediction tools and seven APA detection algorithms using five RNA-seq datasets derived from clear cell renal cell carcinoma (ccRCC) and adjacent normal tissues. By evaluating tool performance across genes with either single or multiple PASs, we revealed substantial variation in accuracy, sensitivity, and consistency among the tools. Based on this comparative analysis, we offer practical guidelines for tool selection and propose considerations for improving APA detection accuracy. Additionally, our analysis identified CCNL2 as a candidate gene exhibiting significant APA regulation in ccRCC, highlighting its potential as a disease-associated biomarker.

Colorectal cancer (CRC) remains a major contributor to cancer-related morbidity and mortality. While Dachshund homolog 1 (DACH1) was recognized as a critical regulator in cancer progression, its role in promoting or suppressing tumor development remains a subject of ongoing debate. This study aimed to elucidate the role of DACH1 in CRC progression and its underlying regulation mechanisms. The expression levels of Methyltransferase 1 (DNMT1) and DACH1, as well as its methylation status were assessed through a combination of TCGA data analysis and experimental validation using immunohistochemistry, PCR, methylation-specific PCR, and bisulfite sequencing RCR on 120 clinical samples, comprising normal mucosa, adenomas, and adenocarcinomas. The relationships among them were evaluated using Pearson or Spearman correlation analysis. The associations between the DACH1 and DNMT1 levels and clinicopathological parameters were examined to determine their clinical relevance. A progressive decrease in DACH1 expression and a concomitant increase in DACH1 promoter methylation and DNMT1 expression were observed from normal mucosa to adenoma and adenocarcinoma tissues. Higher DNMT1 expression and lower DACH1 expression were associated with poorer clinical outcomes, including worse tumor differentiation, lymphatic metastasis, and advanced tumor stages. Paired analysis of tissues from the same patient further validated their inverse expression patterns during CRC progression. DNMT1-mediated DACH1 epigenetic silencing plays a critical role in CRC progression, suggesting that the DNMT1-DACH1 regulatory axis may serve as a potential biomarker and therapeutic target in CRC.

Immune checkpoint blockade (ICB) therapy has shown promise in treating advanced colorectal cancer, particularly in patients with microsatellite instability-high (MSI-H) tumors. However, only a subset of these patients responds favorably, highlighting the need for strategies to improve immunotherapy efficacy.

RNA 5-methylcytosine (m5C) modification is a crucial epitranscriptomic mark that regulates RNA stability, processing, and translation. Emerging evidence highlights its essential role in various physiological processes, including cellular differentiation, stem cell maintenance, and immune responses. Dysregulation of m5C modification has been implicated in multiple pathological conditions, particularly in cancer, neurodegenerative disorders, and metabolic diseases. This review provides a comprehensive overview of the molecular mechanisms governing m5C deposition, its functional consequences in normal physiology, and its contributions to disease pathogenesis. Furthermore, we discuss the potential of m5C as a biomarker and therapeutic target, offering new insights into its biological significance and clinical relevance.

Activated phosphoinositide-3-kinase-delta (PI3Kδ) syndrome (APDS) is an autosomal dominant inborn error of immunity (IEI) characterized by combined immunodeficiency and immune dysregulation with increased risk for lymphoma and other non-lymphoid malignancies. We describe five patients with ovarian malignancies among 110 female APDS patients participating in the European Society for Immunodeficiencies (ESID) registry and identified three additional cases in the literature. These findings document a relevant predisposition to these non-hematological malignancies in APDS patients.

Breast cancer significantly affects women's lives globally. While PAX7 (Paired Box 7), a regulatory protein linked to muscle growth, has been connected to various cancers, its role in breast cancer is not well understood. This study explores PAX7's significance in breast cancer and its mechanisms. RNA-seq data from the TCGA database assessed PAX7 expression across cancer types. Prognostic value in breast cancer was evaluated using Kaplan-Meier and Cox regression analyses. Functional experiments, including high-throughput sequencing, cell growth analysis, colony formation, Transwell assays, and Western blot analysis, were conducted on PAX7 knockdown cell lines (MDA-MB-468 and MDA-MB-231). Results showed high PAX7 expression in breast cancer linked to lower survival rates. PAX7 knockdown affected over 2000 genes and inhibited cancer cell proliferation, migration, and invasion, involving the Wnt/β-catenin pathway. SKL2001 reversed these effects. PAX7 is a potential prognostic biomarker and therapeutic target, with elevated levels indicating a poor prognosis. Further research on PAX7-targeted therapies is needed.

Methyl eugenol (ME), a natural compound found in various essential oils, has recently been classified as a Group 2A carcinogen by the International Agency for Research on Cancer.

Chromosomal 11q13.3 amplification is the most common gene copy-number variation event in head and neck squamous cell carcinoma (HNSCC) that corresponds with poor prognosis. Although cyclin D1, a G1/S phase cell-cycle regulatory protein at this locus, is considered as a key driver of malignant progression, further exploration is needed to develop more effective targets for cases with this amplification. Using CRISPR-based gene knockout screening of genes located in chr11q13.3, we found that loss of the gene encoding the Fas-associated death domain (FADD) protein, a well-recognized adapter to caspase-8 that induces cell apoptosis, significantly reduced cancer cell proliferation. FADD expression was elevated in chr11q13.3-amplified tumors and correlated with poor prognosis. RNA sequencing, mass spectrometry, and proteomics analyses revealed a direct relationship between FADD and the DNA helicase MCM5 in the S phase. FADD and cyclin D1 acted at different stages of the cell cycle to synergistically induce proliferation, and caspase-8 deficiency was required for the oncogenic activity of FADD. In a patient-derived xenograft model with chr11q13.3 amplification, combined administration of the DNA helicase complex inhibitor and CDK4/6 inhibitor effectively curtailed tumor growth. Overall, this study identified a nonclassic oncogenic role for FADD in mediating tumor progression in HNSCC and provided a feasible treatment option for patients with chr11q13.3 amplification. Significance: FADD promotes progression of tumors with chr11q13.3 amplification by binding to the DNA helicase complex, which can be targeted in combination with cyclin D1 as a viable therapeutic strategy for HNSCC patients.

RNA 5-methylcytosine (m5C) modification has emerged as an important regulatory mechanism in the progression of human cancers, including hepatobiliary tumors. The m5C "reader" Aly/REF export factor (ALYREF) was recently found to be identified as a prognostic biomarker in liver cancer. However, its exact role in intrahepatic cholangiocarcinoma (ICC) progression is unclear. In this study, ALYREF was found to be upregulated in ICC tissues and cells. The gain- and loss-of-function experiments indicated that ALYREF promoted cell proliferation and invasion and suppressed cell apoptosis. Moreover, we found that isocitrate dehydrogenase 1 (IDH1), a metastatic marker of liver cancer, was also upregulated in ICC tissues, displayed a relatively strong positive correlation with the level of ALYREF, and was positively regulated by ALYREF. As an m5C "reader", ALYREF interacted with m5C-IDH1 mRNA and increased its stability. ALYREF knockdown partially eliminated the promotion of IDH1 on ICC cell proliferation and invasion. ALYREF positively regulated NRF2-driven glutathione synthesis in ICC cells, which was reversed by IDH1 silencing. Finally, in a xenograft tumor mouse model, knockdown of ALYREF or treatment with ivosidenib (an IDH1 inhibitor) significantly suppressed tumor growth in vivo. In conclusion, ALYREF promotes ICC progression by increasing IDH1 levels in an m5C-dependent manner.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of lymphoproliferative disorders characterised by skin infiltration by malignant memory T cells. While most patients will present with an indolent disease, others will follow a highly aggressive clinical course. Currently, defining disease prognosis remains challenging. Ectopic expression of gametocyte-specific factor 1 (GTSF1) has emerged as a potential prognostic biomarker. However, its contribution to CTCL carcinogenesis remains unknown. Here, we report that GTSF1 contributes to carcinogenesis by partially modifying the memory/effector phenotype of the malignant T cells. GTSF1 knockdown in CTCL cells led to T-cell activation and production of IFNγ and TNFα. Advanced stages of the disease are associated with decreased production of these cytokines. Notably, we show that patients classified with high expression of GTSF1 are associated with a worse disease prognosis. Taken together, our findings indicate that GTSF1 expression in CTCL cells allows them to acquire memory T-cell phenotype. Malignant memory T cells have a decreased production of immune-responsive cytokines, leading to a diminished immune response and disease progression. GTSF1 is an important candidate as a prognostic biomarker. Furthermore, understanding the specific function of GTSF1 might help develop novel targeted treatment options for CTCL patients.

Emerging evidence highlights the critical involvement of dysregulated circular RNAs (circRNAs) in non-small cell lung cancer (NSCLC) pathogenesis. Nevertheless, the precise functional role and mechanistic contributions of circ-MBOAT2 in NSCLC remain poorly characterized. The purpose of this study was to investigate the pathogenesis of NSCLC based on circ-MBOAT2.

Our aim was to identify crucial RNA-binding proteins (RBP) genes associated with Ewing sarcoma (EwS) in order to provide valuable insights into its mechanisms of tumorigenesis and to enhance therapeutic intervention.

Ovarian Cancer (OC) is a gynecological malignant tumor with an extremely high mortality rate, seriously endangering women's health. Due to its insidious clinical manifestations, most patients are diagnosed in the advanced stage of the disease. The currently clinically relied CA125 has limited specificity for the early diagnosis of ovarian cancer. Hence, identifying new promising biomarkers is crucial for the early screening, diagnosis, and treatment of ovarian cancer. Based on differential expression analysis, WGCNA and survival analysis, we identified a centromere-associated gene, WDR62, which is highly expressed in ovarian cancer and highly correlated with ovarian cancer, as well as the poor prognosis of ovarian cancer patients with high expression, suggesting that WDR62 may be a potential biomarker for ovarian cancer. Previous studies have shown that WDR62 is closely associated with the occurrence, development and prognosis of a variety of tumors. However, its role in ovarian cancer has not been studied in depth.

T-cell acute lymphoblastic leukemia (T-ALL) is a relatively rare hematological malignancy, characterized by the uncontrolled proliferation of immature T lymphoblasts and associated with a generally unfavorable prognosis. Our previous research has demonstrated that decreased mitochondrial activity is associated with the aggressiveness of T-ALL tumors. However, the mechanisms underlying this phenomenon and its contribution to treatment resistance remain largely elusive.