Cancer Cell International最新文献

SLC25A13, a pivotal component of the mitochondrial aspartate-glutamate carrier, is integral to cellular metabolism and has been linked to various diseases. However, its role in cancer biology remains largely unexplored. In this study, we employed multi-omics data to elucidate the genetic landscape, expression profile, and prognostic value of SLC25A13 in a pan-cancer context. Additionally, we examined the correlation between SLC25A13 and the immune microenvironment across various cancers. By applying multiple machine learning methods, we identified seven core SLC25A13 co-expressed genes and developed a nomogram to predict the prognosis of glioma patients, validating its efficacy across multiple independent datasets. Furthermore, in vitro and in vivo experiments demonstrated that SLC25A13 is significantly overexpressed in glioblastoma tissues compared to paraneoplastic tissues, promoting glioblastoma cell proliferation and migration while inhibiting apoptosis. Collectively, our study positions SLC25A13 as a promising biomarker for cancer prognosis and a potential therapeutic target, particularly in glioma, thereby laying the groundwork for future research into its therapeutic exploitation in cancer.

Background: Glioma is the most common primary malignant tumor of the central nervous system, and due to the limited effectiveness of traditional single-target therapies, there is an urgent need for new therapeutic targets. Centromere protein F (CENPF) belongs to the centromere protein family and is mainly involved in the regulation of the cell cycle. CENPF has recently been found to play a key role in tumorigenesis and tumor progression, but its role in gliomas has not been well studied.

Methods: The expression level and clinical information of CENPF were obtained by analyzing the TCGA, CGGA and GEO databases. Immunohistochemistry and western blot analysis were used to quantitatively detect the expression of CENPF in glioma tissues and cell lines. Gene set enrichment analysis (GSEA) of TCGA and GSE16011 datasets was used to explore the molecular mechanism of the CENPF. CENPF-interacting proteins were detected by molecular docking and co-immunoprecipitation (Co-IP). After silencing CENPF, CCK-8 assay, Transwell assay and flow cytometry were used to detect changes in cell proliferation, invasion, cell cycle and apoptosis, and Western blot was used to detect changes in signaling pathway protein levels.

Results: Bioinformatics analysis showed that CENPF was generally highly expressed in gliomas and was associated with poor prognosis. This result was confirmed in glioma samples from our hospital. Multivariate Cox regression analysis showed that CENPF was an independent prognostic marker for gliomas. Western blot analysis in vitro showed that CENPF was overexpressed in the U251 and LN229 cell lines; therefore, these two cell lines were selected for subsequent experiments. GSEA analysis showed that CENPF was mainly involved in the G2/M phase-mediated cell cycle and P53 signaling pathway. Flow cytometry analysis confirmed that silencing CENPF induced G2/M phase arrest and increased apoptosis in glioma cells. Subsequent experiments confirmed that CENPF influences the epithelial-mesenchymal transition (EMT) process through the mTORC1 signaling pathway. Molecular docking and Co-IP assay revealed that CENPF exerts its effects by interacting with PLA2G4A promoting the downstream signaling pathway. Finally, we found that silencing CENPF combined with a PLA2G4A inhibitor (AACOCF3) induced glioma cell apoptosis and exhibited anti-glioma effects.

Conclusions: This study found that CENPF plays a key role in promoting tumorigenesis through its interaction with PLA2G4A. This study provides a theoretical foundation for advancing multi-targeted therapies in glioma and for developing strategies to overcome tumor drug resistance.

Background: Esophageal squamous cell carcinoma (ESCC) is a prevalent and aggressive subtype of esophageal cancer, posing a significant mortality and economic burden, especially in East and Southeast Asia. Current therapeutic strategies have limitations in improving patient survival, particularly regarding disease progression and resistance. This study aimed to investigate the impact of neoadjuvant chemoradiotherapy (NCRT) on the ESCC microenvironment.

Methods: We utilized single-cell RNA sequencing to systematically characterize the tumor and cancer-associated fibroblasts (CAFs) subtypes. Marker genes of myofibroblastic CAFs (myCAFs) were employed to establish a prognostic model and verify its application in other datasets. Other experiments were conducted on clinical samples to explore potential ESCC risk-related genes.

Results: Our bioinformatics and statistical analyses revealed an increased proportion of fibroblasts and epithelial cells in NCRT and identified the Ep_c1 subtype associated with a better prognosis. Further results indicated a complex communication network between Ep_c1 and myCAFs. The top 30 marker genes of myCAFs were used to construct a prognostic signature with a significant response to immunotherapy. Finally, experiments identified Complement C1s subcomponent (C1S), Decorin (DCN), and Neuroblastoma suppression of tumorigenicity 1 (NBL1) as potential ESCC risk-related genes.

Conclusion: Our findings highlight the dynamic alterations in the post-NCRT ESCC microenvironment and provide a foundation for the development of personalized treatment and immunotherapeutic approaches. Future studies are warranted to further validate these findings and explore their clinical implications.

Background: At present, there is no effective prognostic indicator for muscle invasive bladder cancer (MIBC). A liquid biopsy method, plasma circulating tumor DNA (ctDNA) detection, was evaluated for use in predicting the prognosis of different cancers. This study aims to assess the prognostic value of ctDNA state for muscle-invasive bladder cancer patients.

Methods: We comprehensively searched three public databases (PubMed, EMBASE, and the Cochrane Library) in December 2023 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Studies investigating ctDNA and prognostic outcome indicators in patients with MIBC were included in our analysis. The hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted to evaluate the association between ctDNA and the prognosis in patients with MIBC.

Results: Eleven studies and 1,170 patients diagnosed with muscle-invasive bladder cancer, comprising a total of four retrospective cohort studies and eight prospective cohort studies, included in our meta-analysis, one of which had two different cohorts. The analysis revealed that a positive ctDNA state was associated with poor overall survival (OS), progression-free survival (PFS), and recurrence-free survival (RFS) in patients with MIBC (HR = 4.51, 95% CI: 2.64-7.69, P < 0.001; HR = 4.50, 95% CI: 2.77-7.30, P < 0.001; HR = 6.56, 95% CI: 4.18-10.30, P < 0.001), with significant prognostic effects both pre- and post-treatment. In addition, longitudinal ctDNA analysis proved to be effective in the monitoring of patients with MIBC receiving different treatments (HR = 0.24, 95% CI: 0.14-0.41, P < 0.001).

Conclusions: A positive ctDNA state was associated with poor OS, PFS, and RFS in patients with MIBC pre- and post-treatment. Meanwhile, clearance of ctDNA was associated with improved RFS in patients with MIBC. These findings suggest that the ctDNA state is a predictive and prognostic indicator for patients with MIBC, which can be used to monitor recurrence and guide treatment. Thus, ctDNA level detection shows potential for the treatment and prognosis of patients with MIBC.

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is one of the first truncal events in clear cell Renal Cell Carcinoma (ccRCC) tumorigenesis. The accumulation of Hypoxia Induced Factor (HIFα) resulting from VHL loss can promote ccRCC tumorigenesis by regulating microRNA (miRNA) expression. Here, we performed miRNA profiling and high-throughput analysis to identify a panel of VHL-dependent miRNAs in ccRCC. Validation of these miRNAs revealed the overexpression of miR-2355-5p in ccRCC cell models and primary tumors. Moreover, we showed a significant increase in circulating miR-2355-5p in plasma from patients with ccRCC. Mechanistically, miR-2355-5p overexpression was confirmed to be HIF-2α dependent. Targeting miR-2355-5p with the CRISPR/Cas9 system not only negatively disrupted the ability of ccRCC cells to stimulate angiogenesis but also decreased cell proliferation and drastically reduced tumor growth in mouse xenograft models. Finally, a miR-2355-5p pulldown assay identified five tumor suppressor genes, ACO1, BTG2, CMTM4, SLIT2, and WDFY2, as potential targets. All five genes were significantly downregulated in ccRCC tumors and mouse xenograft tumors. The results from this research demonstrate the oncogenic ability of miR-2355-5p and shed light on the possible mechanism by which this miRNA controls angiogenesis and tumor growth in VHL-deficient ccRCC.

E3 ubiquitin ligases are acknowledged as the principal catalysts in the ubiquitination process due to their capacity to identify, bind and recruit specific substrates for modification. However, knowledge about the expression patterns of E3 ligases and their contribution to the tumor heterogeneity of bladder cancer (BLCA) is still lacking. Here, we delineated two distinct subcategories of BLCA utilizing consensus clustering of variable expression patterns of E3 ligases from the TCGA database, outlining the functional characteristics and immune profiles of these subclusters. Crucially, these clusters offered valuable perspectives on the tumor immune microenvironment (TIME) and tumor response to immunotherapy. Additionally, we established and validated an E3 ligase-related prognostic model predicated on genes associated with E3 ligases, which robustly foretold the prognosis, TIME, and the efficacy of immunotherapy in BLCA patients. Besides, we systematically interrogated the correlation between the IC50 values of commonly used antitumor drugs and the E3 ligase-related risk score and expression levels of prognostic genes. Notably, we identified and validated that EMP1 inhibition synergized with the antitumor effects of oxaliplatin in T24 and 5637 BLCA cell lines. Furthermore, knockdown of SLC26A8, an E3 ligase-related prognostic gene, significantly promoted tumor progression in BLCA. In summary, we introduced an innovative E3 ligase-based classification framework and prognostic model for BLCA, presenting a potent and auspicious prognostic and immunotherapeutic benefit predictor for individual BLCA patients.

Cancer-associated fibroblast cells (CAFs) play a key role in the breast cancer (BC) microenvironment that induces resistance to chemotherapy. Adipose mesenchymal stem cells (ADMSCs) derived exosomes were utilized to deliver the doxorubicin (Dox) to BC cell lines (MDA-MB-231, MCF-7) and CAFs in both mono and co-culture systems. Immunocytochemistry (ICC) for VIMENTIN and flow cytometry for the CD45, CD34, CD73, and CD90 markers were used to confirm the phenotypic characteristics of CAFs and MSC cells. Dox was loaded into ADMSCs-derived exosomes (Exo-Dox) through sonication and its loading wasa confirmed by transmission electron microscope (TEM). Compared to free Dox, Exo-Dox showed a higher efficiency in inducing apoptosis and inhibiting growth and migration in co-culture cells with CAFs (P < 0.05). The up-regulation of H19 and UCA1 lncRNAs, associated with chemoresistance, was confirmed using real-time PCR in CAF-derived breast cancer patients, CAF-derived exosomes, and exosome-derived patient serums. H19 and UCA1 expression levels were significantly down-regulated in MDA-MB-231, MCF-7, and co-cultures of MDA-MB-231 and MCF-7 cells with CAFs that received Exo-Dox treatment. In vivo results indicated that ADMSCs-derived exosomes (MSC-Exos) can accumulate at the tumor site. Exo-Dox suppressed cancer cell growth and significantly decreased tumor size compared to PBS (p < 0.01). The findings confirmed the growth inhibition effects of Exo-Dox n in CAFs, BC cells, and tumor-bearing mice.

Tumor-infiltrating immune cells have been widely recognized as playing an important role in the promotion or inhibition of tumor growth. Recently there has been increasing attention on tumor-infiltrating B cells in the tumor microenvironment. However, the role of B cells in non-small cell lung cancer remains largely unknown. Reviewing recent studies, here we describe the distribution, phenotype, and heterogeneity of B lymphocytes in the non-small cell lung cancer, present their functions and discuss the prognostic significance of the different B-cell subtypes as well as potential therapeutic strategies targeting TIL-Bs. Finally, the review highlights the need for future research to further elucidate their precise function in the tumor microenvironment.

Background: α5-nicotinic acetylcholine receptor (α5-nAChR) participates in chronic stress-promoted lung adenocarcinoma (LUAD) progression. Neuropilin and tolloid-like 2 (NETO2) contributes to fear expression and extinction, which is related to tumorigenesis. CHRNA5 (encoding α5-nAChR) gene profiling revealed a reduction in NETO2 expression following CHRNA5 knockdown. Nevertheless, the connection between α5-nAChR and NETO2 in LUAD progression induced by chronic stress remains unclear.

Methods: RNA-Seq and bioinformatics database were used for analyzing the expression as well as correlation of α5-nAChR, together with NETO2 in LUAD. α5-nAChR and NETO2 expression were detected using immunohistochemistry in LUAD tissue microarrays, chronic restraint stress (CRS) and chronic unpredictable stress (CUMS) mice tissues. In lung adenocarcinoma A549 and H1299 cells, the expression of α5-nAChR, NETO2, p-CAMKII, p-STAT3 and vimentin induced by acetylcholine/nicotine was examined by western blot. The interaction of α5-nAChR with NETO2 in lung adenocarcinoma cells was detected by Co-immunoprecipitation assay and modeled using molecular docking. EdU assay and colony formation assay were conducted to evaluate cell proliferation, while wound healing assay as well as transwell assay assessed the migration and invasion of lung adenocarcinoma cells.

Results: α5-nAChR expression was related to NETO2 expression, low survival rate, staging as well as smoking status in LUAD dataset as well as tissue microarrays. The correlation between α5-nAChR and NETO2 was validated in nude mice xenograft tissues. α5-nAChR as well as NETO2 expression correlated in CRS and CUMS mice tissues. In vitro, acetylcholine/nicotine mediated NETO2, p-CAMKII, p-STAT3 and vimentin expression via α5-nAChR. α5-nAChR interacted with NETO2 as well as CAMKII in LUAD cells. α5-nAChR/NETO2 signaling contributed to LUAD cell proliferation, migration and invasion.

Conclusions: The above results uncover a new chronic stress-promoted LUAD signaling pathway: α5-nAChR/NETO2 axis contributes to chronic stress-promoted LUAD cell proliferation, migration and invasion.