Molecular and Cellular Oncology最新文献

Sorting nexin 1 (SNX1), a member of the sorting nexin family, has been implicated in various cellular processes, yet its role in ovarian cancer (OV) remains poorly characterized. In this study, we systematically investigated the expression pattern, prognostic relevance and functional impact of SNX1 in OV. Bioinformatics analysis revealed that SNX1 is significantly downregulated in OV tissues, and its low expression is associated with poor overall and progression-free survival. Gene set enrichment analysis indicated that SNX1 downregulation is linked to activation of cancer-related pathways, including p53 signaling, PI3K/AKT signaling, and cell cycle-associated programs such as E2F targets and G2/M checkpoint. Functionally, SNX1 overexpression inhibited OV cell proliferation, blocked G1/S transition (with downregulation of E2F1, CDK2, CDK6, and cyclin D1), promoted apoptosis, and suppressed cell migration by modulating EMT markers (upregulating E-cadherin; downregulating N-cadherin, vimentin, Snail1, and β-catenin). Drug sensitivity analysis demonstrated a synergistic anti-tumor effect between SNX1 overexpression and paclitaxel treatment. Collectively, our findings identify SNX1 as a tumor suppressor and potential therapeutic target in OV, functioning through regulation of cell cycle, apoptosis and migration.

Acetyl-CoA acyltransferase 1 (ACAA1), encoding the peroxisomal 3-ketoacyl-CoA thiolase (POT1), plays a pivotal role in the fatty acid beta-oxidation pathway. Accumulating evidence has linked this enzyme to the onset and development of diverse human malignancies. Here, we observed a marked downregulation of ACAA1 in nasopharyngeal carcinoma (NPC), which displayed an inverse correlation with the expression genes coded by Epstein-Barr virus (EBV). Receiver operating characteristic (ROC) curve and Kaplan-Meier survival analysis highlighted the potential of ACAA1 as a valuable diagnostic and prognostic biomarker for NPC. Next, gain-of- function experiments were conducted, and the results vividly illustrated that overexpression of ACAA1 potently impeded the proliferation, migration, and invasion of NPC cells. The inhibitory effect was further verified by the reduced Ki-67 staining intensity and the altered distribution pattern of actin filaments, which are crucial indicators of cell proliferation and motility. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed significant enrichment of immune-related pathways in NPC cells with elevated ACAA1 expression. Moreover, comprehensive xCell, ESTIMATE, and Immunophenoscore analyses underscored the positive association between ACAA1 and immune cell infiltration and the tumor immune effective microenvironment in NPC. Especially, a positive correlation between ACAA1 expression in tumor cells and six immune checkpoint-related genes, namely CD27, PDCD1, CD86, BTLA, TIGIT, and CD28, on immune cells within the tumor microenvironment. Collectively, our findings highlight the potential of ACAA1 as a tumor - suppressor gene and suggest its possible involvement in the immune evasion mechanisms of NPC. This study may provide novel insights into the molecular pathogenesis of NPC and offer new therapeutic targets for this malignancy.

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor syndrome caused by pathogenic variants in the NF1 gene. Beside tumor formation, patients often have sleep disturbances, suggesting circadian involvement. Previous NF1 studies have implicated MAPK pathway, cAMP-PKA, calcium signaling, and ALK in circadian regulation, and shown disrupted rhythms in murine astrocytes lacking NF1. However, whether human Schwann cells show rhythmic gene expression remains unknown, although impaired rhythms may contribute to tumorigenesis. In this study, we analyzed normal human Schwann cells and NF1-derived malignant peripheral nerve sheath tumors (MPNST) for rhythmic gene expression. Cultured cells were synchronized via serum shock, and mRNA levels of core clock and associated genes (e.g. ARNTL, JUN, TGFA, CLOCK, VEGFA, MYC) were quantified at defined intervals. We observed rhythmic core clock gene expression in normal Schwann cells, demonstrating intrinsic circadian oscillations in peripheral glia. In contrast, MPNST lacked rhythmicity in core clock genes, instead showing de novo rhythmic expression of oncogenes and growth factors like MYC and VEGFA. Thus, loss of clock gene rhythmicity (desynchronization) and emergence of rhythmic oncogene expression (synchronization) in NF1-associated MPNST further our understanding of peripheral glial physiology and tumorigenesis. These insights suggest that chronotherapeutic strategies may be beneficial for NF1-associated MPNST.

Background and aim: Cytokeratins (CKs) are structural proteins vital to epithelial integrity and play key roles in breast cancer progression. This review explores their expression, functions, and therapeutic potential.

Methods: A systematic review was performed using PubMed, Scopus, and Google Scholar. We focused on in vivo, in vitro, and human studies - as well as review articles - published through 1982 that included keywords such as KRT5/13/16/17/18/19/23/80, Cytokeratin 5/13/16/17/18/19/23/80, Keratin 5/13/16/17/18/19/23/80, CK5/13/16/17/18/19/23/80, Cancer, Tumor, Breast cancer, Triple-negative breast cancer, and TNBC. Following title, abstract, and full-text screening of extracted studies, irrelevant articles and duplicates were excluded.

Results: CK5 and CK17 are strongly associated with aggressive breast cancer subtypes, particularly triple-negative breast cancer (TNBC), influencing tumor invasiveness and drug resistance. CK18 and CK19 play key roles in estrogen receptor signaling and epithelial stability. Newly identified CKs, CK23 and CK80, show strong correlations with metastasis and poor prognosis. CK-driven pathways, such as the Wnt/β-catenin and EMT pathways, contribute to tumor progression and therapy resistance.

Conclusion: CKs are key biomarkers for breast cancer classification, prognosis, and therapy response. Their roles in tumor biology suggest potential for targeted treatment and personalized care to improve outcomes.

XCL1 (lymphotactin), a C-chemokine primarily produced by activated CD8+ T cells, remains poorly characterized in the context of immunotherapy. Here, we conducted comprehensive analyses based on multiple scRNA-seq datasets to identify the presence of XCL1+ CD8+ T cells in hepatocellular carcinoma (HCC) tumor microenvironment. Multiplex Immunohistochemistry and clinical data revealed that the infiltration of this cell population correlated with favorable outcomes. Cell-cell communication demonstrated interactions between XCL1+ CD8+ T cells and NK cells or myeloid cells via CD99 and MIF signaling pathways, respectively. These findings were further supported by spatial transcriptomic data. Using two independent bulk RNA-seq datasets, we found the mean of expression of XCL1 and CD8A could be an independent factor for prognosis of HCC, and next built a prediction score with five marker genes involved in XCL1+ CD8+ T cell population. Our findings proposed that XCL1 may play a key role in anti-tumor immunity and XCL1+ CD8+ T cell population could be a potential target to improve responses for immunotherapy in HCC.

Glioblastoma (GBM) exhibits elevated TRIM22 expression correlated with tumor progression, as validated in TCGA/GEO databases. The effects of TRIM22 knockdown and overexpression on GBM proliferation were evaluated with cellular assays. TRIM22 was identified as a potential Bcl-2 activator via a ubiquitination microarray. Flow cytometry (FCM) was utilized to investigate cell apoptosis. Additionally, the expression levels of Bcl-2 and proteins associated with Bcl-2 were evaluated using Western blot analysis. The interaction and ubiquitination of TRIM22 and Bcl-2 were analyzed via immunoprecipitation (IP). TRIM22 overexpression is correlated with glioma progression, and TRIM22 deficiency inhibits GBM cell proliferation. FCM revealed that TRIM22 knockdown promotes GBM cell apoptosis. A TRIM22-overexpressing ubiquitination microarray identified TRIM22 as a potential activator of Bcl-2. Western blot analysis revealed that TRIM22 increases the protein expression levels of Bcl-2. Ubiquitination assays revealed that TRIM22 promotes the stability of Bcl-2 via nondegradative ubiquitination. IP experiments indicated that TRIM22 binds to Bcl-2. TRIM22 may significantly impact glioma progression by modulating Bcl-2. Previous studies have shown that knockdown of TRIM22 can enhance the sensitivity of temozolomide treatment, so TRIM22 is expected to become a new target for glioma immunotherapy.

Drug resistance remains a major obstacle in neuroblastoma treatment. Lysosomal sequestration, facilitated by the V-ATPase proton pump, is one of the mechanisms of chemoresistance. Overexpression of the ATP6V0D1 subunit of V-ATPase, previously reported in various cancers, was also observed in ellipticine-resistant neuroblastoma cells in our study. Neuroblastoma cells also exhibited increased lysosomal capacity and vacuolation after ellipticine treatment. Knockdown of ATP6V0D1, but not ATP6V1H, enhanced ellipticine sensitivity, suppressed proliferation and migration, decreased lysosomal uptake, and induced G2/M arrest in neuroblastoma cell lines. Notably, inhibiting another V-ATPase subunit, ATP6V1H, had no effect, highlighting the specific role of ATP6V0D1 in drug resistance. Ellipticine-induced vacuolation, identified as endoplasmic reticulum swelling, lacked evidence of paraptosis. ATP6V0D1 knockdown suppressed this phenomenon, whereas ATP6V1H silencing did not. Our findings underscore the importance of ATP6V0D1 in neuroblastoma and suggest potential therapeutic strategies targeting V-ATPase for overcoming drug resistance.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options, underscoring the need for novel therapeutic targets. Metabolic reprogramming is a hallmark of PDAC, enabling tumor cells to sustain rapid proliferation and survive under nutrient-deprived conditions. While glutathione S-transferase pi 1 (GSTP1) is a known regulator of redox homeostasis in PDAC, its role in metabolic adaptation remains unclear. Here, we show that GSTP1 knockdown disrupts PDAC metabolism, leading to downregulation of key metabolic enzymes (ALDH7A1, CPT1A, SLC2A3, PGM1), ATP depletion, mitochondrial dysfunction, and phospholipid remodeling. Phospholipid remodeling, including an increase in phosphatidylcholine (PC) levels, further suggests a compensatory response to metabolic stress. Importantly, GSTP1 knockdown led to elevated lipid peroxidation, increasing 4-hydroxynonenal (4-HNE) accumulation. Treatment with the antioxidant N-acetyl cysteine (NAC) partially restored metabolic gene expression, reinforcing GSTP1's role in the interplay between redox regulation and metabolism in PDAC. By disrupting multiple metabolic pathways, GSTP1 depletion creates potential therapeutic vulnerabilities that could be targeted through metabolic and oxidative stress-inducing therapies to enhance treatment efficacy.

The genes MutL Homolog 1 (MLH1), O6-methylguanine-DNA methyltransferase (MGMT), and cyclin-dependent kinase inhibitor p16INK4a are commonly downregulated by hypermethylation in colorectal cancer. Long interspersed nucleotide element 1 (LINE-1) can be used as marker for global hypomethylation. This study compared MLH1, MGMT, p16INK4a, and LINE-1 methylation with gene expression in colon tumors, matched non-cancerous mucosa, and control mucosa to identify signs of premalignancy. Tissues were obtained from 20 colon cancer patients and 40 controls. CpG site methylation was quantified by pyrosequencing, expression by qPCR, and MSI/KRAS status by fragment analysis and droplet digital PCR. MLH1, MGMT, and p16INK4a methylation was increasingly higher in control mucosa, non-cancerous mucosa, and tumors. MLH1 expression was lower in tumors compared to non-cancerous mucosa but higher compared to control mucosa. Tumoral LINE-1 methylation correlated negatively with MLH1 (r = -0.51, p = .021) and p16INK4a (r = -0.55, p = .012) methylation, but positively (r = 0.74, p = .0002) with MLH1 expression. A p16INK4a SNP (rs3814960 C>T) was associated with methylation, expression, and MSI/KRAS status. Aberrant methylation of tumor suppressor genes in colon mucosa could be an early cancer risk marker. Control mucosa is a more reliable reference than non-cancerous mucosa when identifying premalignant changes. Extended studies will evaluate the possible association between rs3814960 and cancer susceptibility. Trial registration: NCT03072641.

The purpose of the study is mainly to investigate anti proliferation of non-small cell lung cancer A549 cells and its mechanism by inhibition of CHK1 expression combined with gemcitabine. The mRNA and protein levels of genes were analyzed by RT-qPCR and Western blot, respectively. Cell viability was detected by CCK-8 assay and clone formation assay. The detection of the cell cycle was used by Annexin V/7-amino-actinomycin D apoptosis detection kit. Analysis of DNA damage was done by immunofluorescence and alkaline comet assay. The results showed that inhibition of CHK1 and gemcitabine combination significantly reduced the proliferation ability of the two cell lines. We also revealed the degradation of full-length PARP and reduced Bcl-2/Bax ratio on increased apoptosis. Inhibition of CHK1 expression leads to DNA damage, induces phosphorylation of γ-H2AX, and affects the repair of homologous recombination ability through Rad51. Mechanistically, gemcitabine increased phosphorylation-ATR and phosphorylation-CHK1, indicating activation of the DNA repair system and ATR-CHK1-CDC25A pathway. Inhibition of CHK1 resulted in increased synthesis of CDK2/Cyclin A2 and CDK2/Cyclin E1 complexes, and more cells entered the subsequent cell cycle, leading to S phase arrest and mitotic catastrophe. We identified inhibition of CHK1 as a potential treatment for NSCLC and confirmed that inhibition of this kinase could overcome acquired gemcitabine resistance.