Molecular Carcinogenesis最新文献

Ovarian cancer (OC) is a leading cause of cancer-related mortality among females worldwide. Lysine demethylase 6A (KDM6A) plays a crucial role in multiple physiological and pathological processes. However, its role in ovarian carcinogenesis remains unclear. The expression of KDM6A and survival analysis in OC were assessed utilizing GEPIA and Kaplan-Meier plotter databases. The expression of KDM6A was evaluated immunohistochemically in tissue samples from 55 OC patients. The CCK-8, Colony formation, and Transwell assays were employed to assess the ability of OC cells in proliferation, migration, and invasion. Lung metastasis and subcutaneous tumor models were used to evaluate the function of KDM6A in vivo. RNA sequencing, Western blot, and quantitative polymerase chain reaction were conducted to investigate the molecular functions of KDM6A. A chromatin immunoprecipitation assay was employed to determine the effects of KDM6A on the promoters of ubiquitin-like protein interferon-stimulated gene 15 (ISG-15). KDM6A expression was downregulated in OC and associated with poor progression-free survival and overall survival. KDM6A inhibits OC cell proliferation, migration, and invasion in vitro. Xenograft models have also confirmed the antitumor role of KDM6A in OC growth and metastasis. The mechanistic study demonstrated that KDM6A exerted an antitumor effect in a histone-demethylase-dependent manner by epigenetically activating ISG-15 transcription. KDM6A, a functional tumor suppressor, is frequently downregulated in OC. The KDM6A-ISG-15 axis is critical in restraining OC malignancy and may serve as a potential molecular target for novel therapies.

Tertiary lymphoid structures (TLS) demonstrate prognostic significance and associations with immunotherapy response in gastrointestinal malignancies, though their regulatory mechanisms remain incompletely defined. The current understanding of TLS at single-cell resolution is limited. Here, we integrated single-cell and spatial transcriptomics with TLS-specific signatures to map spatial distributions and chemokine signaling within colorectal (CRC) and gastric cancer (GC) microenvironments. We identified significant enrichment of characteristic T cell and macrophage subsets in the TLS regions. Subpopulation analyses revealed distinct cellular interaction networks: CRC exhibited robust intercellular communication among effector CD8⁺ T cells, exhausted CD8⁺ T cells, tissue-resident CD8⁺ T cells, CD16⁺ monocyte-derived macrophages, C1QC⁺ macrophages, and SPP1⁺ macrophages. Conversely, GC featured pronounced interactions between interferon-stimulated gene-positive (ISG⁺) CD8⁺ T cells and ISG15⁺ macrophages. Further analyses suggest CD16⁺ monocyte-derived macrophages may recruit effector CD8⁺ T cells via the CXCL16-CXCR6 ligand-receptor pair in CRC, while ISG15⁺ macrophages may utilize dual CXCL16-CXCR6 and CXCL10-CXCR3 pairs to recruit ISG⁺ effector CD8⁺ T cells in GC. Our study uncovers spatially resolved, cancer-type-specific immune recruitment circuits within TLS, providing mechanistic insights into their functional organization and potential therapeutic targeting.

Linarin is a natural flavonoid glycoside that has extensive pharmacological activities, such as anti-inflammatory, antioxidant, and anticancer effects. However, the functions of linarin in colorectal cancer have not been fully elucidated. The purpose of our study was to investigate the effect of linarin on colorectal cancer and delineate its potential molecular mechanisms. The malignant behavior of colorectal cancer cells were investigated utilizing colony formation, 5-ethynyl-2'-deoxyuridine, Annexin V/PI double staining, scratch, and transwell assays. The potential mechanism of linarin's anticancer activity was explored using network pharmacology analysis, molecular docking, qRT-PCR, immunohistochemical staining, western blot analysis, immunofluorescence, CHX chase assay, ubiquitination assay, and rescue experiments. In addition, mouse xenograft tumor models were used to confirm the role of linarin in colorectal cancer in vivo. We found that linarin inhibited the proliferative, migratory, and invasive abilities, but enhanced the apoptotic ability of colorectal cancer cells. Moreover, we also discovered that linarin could repress HIF-1α expression and HIF-1α/PD-L1 axis in LoVo and HCT-15 cells. Both HIF-1α and PD-L1 overexpression reversed the effect of linarin on the malignant behavior of colorectal cancer cells. Furthermore, linarin treatment significantly inhibited colorectal cancer tumor growth in vivo. In conclusion, linarin could inhibit the proliferative, migratory, and invasive capacity, but enhance the apoptotic ability in colorectal cancer cells through repressing the HIF-1α/PD-L1 axis.

Sphingosine-1-phosphate receptor 1 (S1PR1, also known as EDG1) is a G-protein-coupled receptor. Although there have been conflicting results reported, S1PR1 is generally accepted to be protumorigenic in many cancer types. However, S1PR1 has not been studied in thyroid cancer. This study aimed to investigate the biological activity of S1PR1 in thyroid cancer. S1PR1 protein levels were found to be higher in thyroid cancer tissues than adjacent normal tissues. Using an S1PR1-GFP construct, we showed that S1PR1 is localized in the cell membrane; however, when stimulated by sphingosine-1-phosphate, S1PR1 appeared to move inside in the cells. In functional studies, S1PR1 knock-out cells generated using the CRISPR/Cas9 system exhibited reduced S1PR1 activity, including colony formation, cell migration, and cell invasion. This was accompanied by the inhibition of STAT3, ERK1/2, and AKT kinase activity and cell adhesion protein expression. Furthermore, we screened several anticancer compounds to determine their effects on S1PR1 expression levels in thyroid cancer cells and found that quercetin significantly reduced S1PR1 protein levels in these cells. Overall, our results indicated that S1PR1 expression at the protein level has a positive relationship with thyroid cancer progression, as seen in other cancers. These data also suggest that quercetin is a potential anticancer drug that can target S1PR1-positive cells.

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is characterized by a complex pathogenesis and high mortality rate. Currently, there is a lack of effective therapeutic agents for HCC. This study aimed to identify potential targeted therapeutic compounds for HCC and to validate their mechanisms of action through in vitro and in vivo experiments. Using the Connectivity Map database, we screened compounds capable of influencing the status of core genes and selected those predicted to be nontoxic for experimental validation. Our findings demonstrated that, within a certain concentration range (0-80 μM), Purvalanol A significantly inhibited the viability and proliferation of HCC cell lines Huh7 and Hepa1-6. Notably, the IC50 value for normal human liver cells (THLE-2) was much higher than that for HCC cells, indicating selective cytotoxicity. Purvalanol A also suppressed the migration and invasion abilities of HCC cells, induced G2/M cell cycle arrest, and promoted apoptosis. Additionally, Purvalanol A treatment downregulated the expression of the key gene CDK1 (cyclin-dependent kinases) and the antiapoptotic protein Bcl2 while upregulating the expression of p53, phosphorylated p53 (p-p53), and the p53 downstream proapoptotic protein Bax, moreover, the ratio of p-p53/p53 increased, indicating activation of the p53 pathway. In a mouse xenograft tumor model, Purvalanol A significantly inhibited subcutaneous tumor growth without causing noticeable toxicity to internal organs. In conclusion, the results of this study suggest that Purvalanol A exerts anti-HCC effects by activating the p53 pathway, making it a potential therapeutic compound for the treatment of hepatocellular carcinoma.

Ewing sarcoma (ES) is an aggressive bone malignancy with poor outcomes for chemotherapy-resistant patients, yet the mechanisms underlying vincristine resistance remain unclear. Here, we identify protein kinase inhibitor alpha (PKIA) as a critical driver of chemoresistance through cAMP-EPAC signaling reprogramming. Transcriptomic analysis of vincristine-resistant ES cells revealed PKIA upregulation, which correlated with poor survival in clinical cohorts (HR = 2.14, p < 0.001). Mechanistically, PKIA overexpression elevated intracellular cAMP levels but suppressed PKA activity, instead activating the noncanonical EPAC-Rap1-ERK pathway to promote drug efflux and survival. Pharmacological inhibition of EPAC with ESI-09 reversed resistance (IC~50~ reduction: 52%, p < 0.01), while PKIA knockdown restored vincristine sensitivity in xenografts. Strikingly, PKIA exhibited a dual role, with low expression in primary ES (potentially tumor-suppressive) and high expression in resistant/metastatic tumors (prosurvival), mirroring observations in prostate and hepatocellular cancers. Our work establishes PKIA as a therapeutic vulnerability and supports targeting the cAMP-EPAC axis to overcome chemoresistance in high-risk ES.

Colon cancer treatment remains a clinical challenge. Chaperonin containing TCP1 subunit 6 A (CCT6A) acts as an oncogene in multiple tumors. In this study, we investigated its roles in colon cancer cells. We analyzed CCT6A expression using single-cell datasets and the Gene Expression Profiling Interactive Analysis based on The Cancer Genome Atlas database. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and western blot analysis were used to assess CCT6A expression levels in colon cancer tissues and cell lines. Additionally, specific roles of CCT6A in colon cancer was analyzed using cell counting kit-8, 5-ethynyl-2'-deoxyuridine staining, flow cytometry, wound healing, transwell, boron dipyrromethene staining, western blot analysis, and nude model mice. We found that CCT6A expression levels were significantly elevated in colon cancer tissues compared to those in normal tissues and predicted a worse prognosis. CCT6A induced proliferation, migration, invasion, epithelial-mesenchymal transition, and fatty acid synthesis and suppressed apoptosis in colon cancer cells. Mechanistically, CCT6A promoted colon cancer progression by increasing the cleavage of latency-associated peptide (LAP)-transforming growth factor-β1 (TGF-β1) to mature form of TGF-β and inducing Smad2/3 phosphorylation in colon cancer cells. Overall, CCT6A promoted colon cancer progression by modulating fatty acid metabolism and activating the TGF-β1/Smad signaling, serving as a potential therapeutic target for colon cancer.

Therapy acute myeloid leukemia (AML) is a heterogeneous malignant hematopoietic disease that arises either from an antecedent hematologic disorder, including myelodysplastic syndromes, myeloproliferative neoplasms, aplastic anemia, or as a result of exposure to genotoxic chemotherapeutic agents or radiotherapy (therapy-related AML). In this study, we describe a case of therapy AML after treatment for breast, uterine, and rectal malignancies in a patient with a special fusion gene-RUNX1::HMGN1.

African Americans have the highest colorectal cancer (CRC) mortality rates in the United States. We performed the first genome-wide association study (GWAS) of overall and CRC-specific mortality among African Americans with incident CRC to identify genetic contributors to CRC outcomes. Participants enrolled in the Southern Community Cohort Study in 2002-2009; incident CRC and mortality were identified via state cancer registries and the National Death Index. SNPs were genotyped across the genome via Illumina platforms and imputed using the Michigan Imputation Server with Minimac4. Associations with mortality were estimated as hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox proportional hazards models, adjusted for age, sex, stage, and five principal components for ancestry. In total, 500 Black-identifying participants were analyzed, including 316 deaths and 184 CRC-specific deaths. Two novel loci in linkage disequilibrium (r² = 1) within LTBP1 were associated with higher CRC-specific mortality risk: rs34071846 and rs12712337 (per allele HR: 2.74, CI: 1.91-3.92, p = 3.78 × 10^-8). An additional variant mapped to a gene for a noncoding RNA was associated with CRC-specific mortality: rs10103953 (per allele HR: 0.52, CI: 0.42-0.66, p = 2.03 × 10^-8). One loci mapping to MCTP2 was associated with lower overall mortality risk: rs7171579 (per allele HR: 0.59, CI: 0.50-0.71, p = 2.13 × 10^-8). In conclusion, evidence from the present study supports LTBP1 and MCTP2 as important to CRC mortality.

5-Methylcytosine (m5C) RNA modification contributes to tumor initiation and progression. However, its transcriptome-wide distribution patterns and biological implications in hepatitis B virus (HBV)-negative hepatocellular carcinoma (HCC) remain poorly understood. Therefore, this study employs long-read Nanopore direct RNA sequencing to systematically elucidate the mechanisms of m5C-mediated epigenetic reprogramming in HBV-negative HCC. Paired tumor and adjacent normal tissues from three HBV-negative HCC patients were collected for Nanopore sequencing. Transcriptome-wide m5C sites were profiled using the CHEUI tool, followed by a comprehensive comparison between tumor and adjacent normal tissue groups regarding the number of m5C sites, their genomic distribution characteristics, and the expression levels of m5C regulators. Finally, an integrated analysis of transcriptomic and methylation data was conducted to identify m5C-related prognostic indicators in HCC. Tumor tissues exhibited a global increase in m5C sites abundance, with differential modifications enriched on chromosomes 1-3. Genes harboring m5C modifications were significantly enriched in immune and inflammatory pathways, suggesting a potential role for this epitranscriptomic mark in remodeling the tumor immune microenvironment. Consistent upregulation of m5C regulators, including NSUN family members and ALYREF, at both gene and isoform levels, correlated with increased methylation activity. Elevated m5C coupled with decreased CES3 expression were associated with poorer overall survival. Additionally, TMEM234 showed prognostic significance despite unchanged bulk expression in public datasets. m5C modifications are globally altered in HBV-negative HCC and may contribute to post-transcriptional regulation and aberrant expression. These findings highlight the potential of m5C as both a prognostic biomarker and a therapeutic target in HBV-negative HCC.