Molecular Carcinogenesis最新文献

Brain metastasis in nasopharyngeal carcinoma is a rare but poor prognosis clinical problem. This study aims to investigate the clinical characteristics and identify the genomic profiling of nasopharyngeal carcinoma brain metastasis. Patients with a diagnosis of nasopharyngeal carcinoma who visited at the Fifth Affiliated Hospital of Sun Yat-sen University since January 2013 to December 2023 were retrospectively collected. Clinical data of patients diagnosed with nasopharyngeal carcinoma brain metastasis were extracted. Paraffin blocks of NPC brain metastases were acquired for immunohistochemistry and genetic testing. High-throughput second generation sequencing was performed for genomic analysis. The mutation landscape was further analyzed. Of the 2378 NPC patients from our database, only six were clinically diagnosed with nasopharyngeal carcinoma brain metastasis. Three were pathologically diagnosed with nasopharyngeal carcinoma brain metastasis. The time interval from the first diagnosis of nasopharyngeal carcinoma to brain metastasis was 15-56 months. The common sites of brain metastasis were frontal lobe and cerebellum, and could be single or multiple, cystic or solid lesions. The OS ranged from 7 to 48 months. Single nucleotide variants were found in 32 genes, such as PTEN, TP53, NFKBIA, KMT2C, and NOTCH1. Copy number variation occurred in five genes, including PTEN, CCDN1, FGF19, FGF3 and FGF4. PTEN and fibroblast growth factors might be involved in the molecular regulation of brain metastasis in nasopharyngeal carcinoma.

Leukemia is found in approximately 2.3 million people worldwide and causes many deaths all over the world. This research study was conducted to figure out the link of single nucleotide polymorphisms of genes CEBPA (rs34529039), NPM1 (rs753788683), IDH1 (of rs11554137) and RUNX1 (rs13051066) polymorphisms as biomarker potential in leukemia patients. A total of 600 subjects were included in the study which included 300 patients and 300 healthy controls with age and gender matched. After DNA extraction, PCR was carried out to analyze polymorphisms of selected genes. A significant association with increased risk of leukemia by almost twofolds is observed in homozygous mutant (AA) of rs34529039 SNP of gene CEBPA (odds ratio [OR] = 1.71; 95% confidence interval [CI] = 1.04-2.82; p = 0.03) while highly significant association but with decrease risk of leukemia is observed in heterozygote genotype (CA) of same SNP (OR = 0.36; 95% CI = 0.22-0.59; p = 0.0001). A highly significant association with increased risk of leukemia up to twofolds is observed in heterozygote genotype (AG) of rs753788683 of gene NPM1 (OR 2.10: 95% CI 1.32-3.36 p = 0.0017) while increasing risk by two-fold and show significant association in homozygous mutant (AA) (OR = 1.75; 95% Cl = 1.09-2.79; p = 0.01). Leukemia risk increases by twofold and shows significant association in the homozygous mutant (AA) of rs11554137 (OR = 1.75; 95%Cl = 1.09-2.79; p = 0.01). Leukemia risk increases by twofold and shows significant association in the homozygous mutant (AA) of rs13051066 of gene RUNX1 (OR = 0.63; 95%Cl = 0.39-1.63; p = 0.06).

Breast cancer remains a leading cause of cancer-related mortality among women, with current therapeutic approaches often limited by resistance and recurrence, especially in aggressive subtypes like triple-negative breast cancer. Drug repurposing has emerged as a promising strategy to address these challenges. In this study, we investigate the potential of Imatinib, a repurposed tyrosine kinase inhibitor, to inhibit epithelial-mesenchymal transition (EMT) in breast cancer cells by modulating the Notch signalling pathway. Our findings reveal that Imatinib treatment leads to a significant reduction in cancer cell stemness, invasiveness, and migration potential, alongside decreased colony-forming ability. EMT reversal was marked by a 2.71-fold increase in E-cadherin expression, with concurrent downregulation of mesenchymal markers, including Fibronectin (1.78-fold) and Slug (2.15-fold). Mechanistically, Imatinib was found to inhibit p300 acetyltransferase activity, resulting in reduced levels of H3K18Ac and H3K27Ac, which in turn led to the downregulation of key Notch pathway proteins such as HES1 (2.94-fold), AKT (2.08-fold), and p21 (1.88-fold). These results highlight the ability of Imatinib to suppress EMT through modulation of the Notch signalling pathway, offering a novel therapeutic avenue for breast cancer treatment. Overall, Imatinib demonstrates considerable potential for repurposing in breast cancer management by targeting critical oncogenic pathways involved in EMT and cancer progression.

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. Dosage suppressor of NNF1 (DSN1), a component of the MIS12 kinetochore complex, encodes a kinetochore protein crucial for proper mitotic assembly. The role of DSN1 in HCC remains to be elucidated. In this study, we utilized The Cancer Genome Atlas, the Hepatocellular carcinoma Cell Database, and other databases to analyze DSN1 expression and prognosis in samples from patients with HCC. We investigated the signaling pathways regulated by DSN1 and their implications in HCC. Additionally, we engineered siRNAsiRNA/shRNA/shRNA and overexpression vectors for DSN1 and assessed the specific mechanisms of regulatory pathways of DSN1 in hepatoma cell lines and subcutaneous tumor xenograft model. Our findings revealed that DSN1 expression was significantly upregulated in patients with HCC, correlating with decreased survival rates. Elevated DSN1 expression led to the overproduction of cell cycle-related proteins through direct interaction with Centromere Protein T. This interaction contributes to chromosomal instability in patients with HCC, resulting in an aberrant cell cycle and fostering the development and progression of HCC. Increased DSN1 expression is pivotal in HCC initiation and progression. Investigating DSN1 offers valuable insights into the pathogenesis, treatment, and prevention of HCC.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer characterized by a poor prognosis. Despite Zinc finger proteins (ZNFs) importance in tumor development and progression, it is unknown how dysregulated ZNF263 contributes to intrahepatic cholangiocarcinoma. This study aimed to determine whether ZNF263 plays an oncogenic role in ICC progression. The microarray of tumor tissues from clinical intrahepatic cholangiocarcinoma was immunohistochemically analyzed for ZNF263. Based on plate colony formation, CCK8, and tumor xenograft models, ZNF263 was assessed for its biological function. Mechanistically, CUT&Tag, RNA-seq, CHIP-PCR, Dual luciferase reporter assay, Western blotting, transmission electron microscopy (TEM), and immunohistochemical staining were employed. ZNF263 expression was elevated in intrahepatic cholangiocarcinoma tissues compared to nontumor tissues, which negatively impacted patient outcomes. Notably, ZNF263 overexpression promoted ICC cells proliferation via enhancing autophagy, whereas ZNF263 knockdown inhibited ICC cells proliferation. Furthermore, ZNF263 binds to the enhancer region of ULK1 and mediates its expression. ULK1 over-expressing ameliorated ZNF263 knockdown-induced inhibition of CRC proliferation. By activating the ULK1-autophagy axis, ZNF263 promotes proliferation of ICC and is potentially a prognostic or therapeutic target of ICC.

Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC). However, the efficacy of MIBC for chemotherapy is only about 40%. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. In MIBC, the predictive role of NETs in chemotherapy resistance is unclear. We used the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression analyses to develop a NETs-associated signature score (NETs-score) for therapeutic response prediction in the discovery cohort (GSE169455). Then the NETs score-based risk stratification was verified in two validation cohorts (Taber et al.'s cohort, our institutional cohort). In the training cohort, high NETs-score was associated with poor chemotherapy response (AUC = 0.781) and reduced recurrence-free survival (RFS) (hazard ratio [HR] = 2.07, 95% confidence interval [CI]: [1.26-3.40], p = 0.003) in MIBC patients. The NETs-score was also demonstrated to be a predictive factor for the efficacy of neoadjuvant chemotherapy in the validation cohort (AUC = 0.731). The accuracy of the NETs-score was superior to other chemotherapy response predictors such as Ba/Sq expression subtype (AUC = 0.711), BRCA2 mutation (AUC = 0.692) and ERCC2 mutation (AUC = 0.548). Furthermore, in our center cohort, the expression level of H3Cit showed a significant difference between the response and no-response group (p = 0.01). Through immunohistochemical validation, NETs was an independent predictor of MIBC neoadjuvant chemotherapy efficacy as determined by the multivariate logistic regression analysis (OR = 5.94, 95% CI: 1.20-45.50, p = 0.045). Patients with high levels of NETs predicted poor response to neoadjuvant chemotherapy. This study was the first to reveal the correlation between the level of NETs in MIBC and the efficacy of chemotherapy, which may provide a theoretical basis regarding NETs inhibitors.

The role of TGF-β signaling in the epigenetic modifications involved in ovarian cancer is not fully understood. This study investigated the relationship between TGF-β signaling, epigenetic modifications, and cellular behaviors in ovarian cancer. We found that E-cadherin, a key cell adhesion molecule, underwent epigenetic silencing via promoter DNA hypermethylation in ovarian cancer cell lines and that this was accompanied by the upregulation of vimentin, which is indicative of a mesenchymal and invasive phenotype. DNA-demethylating agents restored E-cadherin expression, which suggests that TGF-β signaling mediates this epigenetic silencing. Overexpression of SMAD7, an inhibitory component of TGF-β signaling, reversed E-cadherin silencing, which suggests a role of SMAD7 in modulating the epigenetic status. Functionally, SMAD7 overexpression inhibited the migration and invasion in ovarian cancer cells, which suggests its therapeutic potential for suppressing metastasis. Clinically, ovarian cancer patients with high SMAD7 expression had significantly longer disease-free survival. Mechanistically, SMAD7 overexpression decreased the acetylation of H3K9 and the binding of the transcriptional repressor TWIST1 at the E-cadherin promoter, which promoted its demethylation and reactivation. Disruption of TGF-β signaling upregulated SMAD4 target genes, which are silenced by epigenetic mechanisms, a finding that suggests broader therapeutic implications. Overall, our results provide insights into the role of TGF-β-mediated epigenetic regulation in ovarian cancer metastasis and underscore the therapeutic potential of targeting TGF-β signaling and its downstream effectors. Further research is needed to elucidate the underlying mechanisms and validate these therapeutic strategies.

Mesenchymal glioma stem cells (MES-GSCs) are a major subtype of GSCs that reside within glioma tissues and contribute to metastasis, therapy resistance, and glioma recurrence. However, the precise molecular mechanisms governing MES-GSC functions remain elusive. Our findings revealed that expression levels of miR-505-5p/-3p are elevated in MES-GSCs compared with those in proneural (PN)-GSCs, glioma cell lines, and normal brain tissue and that miR-505-5p/-3p expression levels are decreased in differentiated MES-GSCs. We assumed that miR-505-5p/-3p would play distinctive roles in MES-GSCs and performed loss-of-function experiments targeting miR-505-5p/-3p. Knockdown of miR-505-5p/-3p increased proliferation and promoted differentiation in MES-GSCs while suppressing invasion, temozolomide resistance, and enhancing apoptosis in MES-GSCs. Mechanistically, miR-505-5p/-3p directly targets the 3' UTR of AUF1, leading to its repression in MES-GSCs. Notably, AUF1 expression levels were significantly lower in MES-GSCs compared with those in PN-GSCs, glioma cell lines, and normal brain tissues. Co-inhibition of AUF1 expression with miR-505-5p/-3p knockdown ameliorated the observed cellular phenotypes caused by miR-505-5p/-3p knockdown in MES-GSCs. These results suggest that miR-505-5p/-3p exerts MES-GSC-specific roles in regulating proliferation, differentiation, invasion, apoptosis, and temozolomide resistance by repressing AUF1 expression.

Clear cell renal cell carcinoma (ccRCC) is characterized by its aggressive invasion and metastasis, presenting significant clinical challenges. Gaining insights into the molecular mechanisms underlying its progression is crucial for the development of effective therapeutic strategies. Addressing a critical knowledge gap in understanding ccRCC tumorigenesis, this study aims to elucidate the expression patterns of TRIM21 in ccRCC, unravel its impact on ccRCC patient prognosis, and investigate the regulatory role of TRIM21 in ASS1 expression and urea cycle dysregulation within the context of ccRCC. The results demonstrate that TRIM21 is downregulated in ccRCC, and low expression of TRIM21 predicts an unfavorable prognosis for ccRCC patients. Furthermore, the upregulation of TRIM21 can inhibit the migration and invasion of ccRCC cells by regulating the ubiquitination modification of ASS1. This not only expands the functional role of TRIM21 in ccRCC tumorigenesis but also demonstrates its ability to reverse urea cycle dysregulation through stabilizing ASS1 expression. Specifically, abnormal downregulation of TRIM21 in ccRCC reduces K63 ubiquitination modification of ASS1, leading to decreased stability of the ASS1 protein, aggravated urea cycle dysregulation, and facilitated migration and invasion of ccRCC cells. Additionally, reduction in ASS1 reverses the depressed migration and invasion caused by overexpression of TRIM21 in ccRCC cells. In summary, our findings contribute to a deeper understanding of the functional role played by TRIM21 in ccRCC progression, pinpoint a unique and novel regulatory mechanism involving ectopic downregulation-mediated ASS1 ubiquitination modification and urea cycle dysfunction during ccRCC progression, and provide fresh insights for further investigation into the pathogenesis and metabolic reprogramming associated with ccRCC.