Neoplasma最新文献

Gastric cancer is one of the most common and deadliest malignancies worldwide. Better knowledge of the risk factors for gastric cancer is essential for risk classification and therapeutic strategy evolution in gastric cancer patients. Many kinds of miRNA clusters participate in tumorigenesis and tumor progression. Herein, we sought to screen and certify the crucial miRNA cluster for prognosis prediction and potential therapeutic targets in gastric cancer. The results showed that the mir-371a-373 cluster was the most highly expressed miRNA cluster in gastric cancer. The high expression of the mir-371a-373 cluster (mir-371a, mir-372, and mir-373) was positively associated with the poor overall survival of gastric cancer patients. The expression of mir-373 was correlated with early gastric cancer recurrence. mir-373 was an independent risk factor for gastric cancer recurrence and mortality. Then, gain- and loss-of-function experiments demonstrated that mir-373 could promote the malignancy of gastric cancer cells in vitro and in vivo. Through bioinformatics analysis and experimental validation, mir-373 was correlated with tumor regulation, and ZFP91 was the direct target of mir-373. Our findings suggest that the miR-371-373 cluster, especially mir-373, could be a robust marker for the prognosis prediction of gastric cancer and a potential therapeutic target for gastric cancer.

The progression of cancer strongly depends on the tumor microenvironment and immune surveillance. Tumor necrosis factor alpha (TNFα), a key inflammatory cytokine, can drive both tumor elimination and promotion, depending on its dose and the type of cancer. Colorectal cancer cell lines HCT 116, HT-29, and melanoma cells A375 engineered to stably overexpress the human TNFα gene were used to induce experimental subcutaneous tumors in two immunodeficient mouse strains: athymic Balb/c-nu/nu and SCID/bg mice. In athymic mice, TNFα-overexpressing cells completely lost their tumorigenicity. In SCID/bg mice, with no mature T and B cells and defective NK cells, the TNFα-overexpressing cells formed rudimentary flat ulcerous xenografts with rapidly reduced size, with tumor penetrance of 50-85%. Histopathological analysis revealed necrotic lesions, a more differentiated phenotype of tumor cells forming pseudoglandular structures, and more abundant stromal cells. Intratumoral infiltration of immune cells increased in TNFα-secreting tumors. Positivity of cytokeratins 7 and 20 in colorectal cancer xenografts was decreased. Paradoxically, the expression of ALDH1A1 and ALDH1A3 isoforms, which are important for disease prognosis, was increased. Our study suggests that careful modulation of the tumor microenvironment to a tumor-suppressive one using cytokine TNFα and controlled stimulation of antitumor immunity can contribute to the improvement of cancer treatment.

Gastric cancer (GC) ranks as the fifth most common malignancy globally. Aberrant alternative splicing is implicated in tumorigenesis and progression. SF3B3, a key subunit of the spliceosome complex, is closely linked to alternative splicing dysfunction when its expression is dysregulated. This study delved into SF3B3's role and mechanisms in GC, aiming to uncover novel precision treatment targets. Through TCGA database analysis, SF3B3 was found to be upregulated in GC tissues, associated with poor prognosis and immune infiltration. In vitro experiments included cell culture, transduction, CCK-8, colony formation, scratch, migration, apoptosis assays, cell cycle analysis, and western blot, demonstrating that SF3B3 knockdown curbed GC cell proliferation, migration, and invasion, induced apoptosis and cell cycle arrest, while its overexpression had opposite effects. In vivo xenograft experiments showed that SF3B3 suppression markedly inhibits tumor growth. Transcriptome analysis and western blot suggested that SF3B3 promotes GC cell proliferation and impedes apoptosis by activating the MAPK pathway. Moreover, transcription factor ELK1 was shown to regulate SF3B3 expression, with a significant positive correlation between them. Overall, SF3B3 likely drives GC progression via the ELK1-SF3B3-MAPK axis, representing a potential precision treatment target for GC.

Anillin (ANLN), an actin-binding protein, has been implicated in tumorigenesis across various cancers; however, its role in nasopharyngeal carcinoma (NPC) remains largely undefined. In this study, we analyzed ANLN expression using TCGA, CPTAC, and GEO datasets, and confirmed its overexpression in NPC tissues and cell lines through qRT-PCR, western blotting, and immunohistochemistry. High ANLN expression correlated with advanced clinical stage and poor overall survival. Functional assays, including CCK-8 and colony formation, demonstrated that ANLN knockdown suppressed NPC cell proliferation in vitro, while xenograft models confirmed reduced tumor growth in vivo. RNA sequencing and gene set enrichment analysis revealed that ANLN knockdown was associated with downregulation of ribosome biogenesis pathways. Puromycin incorporation assays and transmission electron microscopy further supported impaired protein synthesis and nucleolar disruption following ANLN depletion. These findings suggest that ANLN promotes NPC progression by maintaining ribosome biogenesis and protein synthesis and may serve as a novel prognostic biomarker and therapeutic target.

Lung cancer is the leading cause of death and the most diagnosed cancer worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer; 85% of lung cancer patients are diagnosed with NSCLC. Though numerous treatments for lung cancer have been developed, the 5-year survival rate of patients with NSCLC remains low. Therefore, it is urgent to explore novel targets for NSCLC treatment. Growing evidence has revealed that circular RNAs (circRNAs) contribute to NSCLC progression. Besides, the data of circRNA microarray (GSE158695) has found that hsa_circ_0011536 is downregulated in NSCLC tissues. Nevertheless, the role of hsa_circ_0011536 in NSCLC remains unknown. In this study, RNA 6-methyladenosine (m6A) modification was detected by methylated RNA immunoprecipitation, the interaction of RNAs was determined using miRNA pulldown and luciferase reporter assay, while ferroptosis was identified by Cell Counting Kit-8 assay, intracellular iron content, and malondialdehyde level. Our findings demonstrated that hsa_circ_0011536 was downregulated in NSCLC cell lines. Mechanism investigation revealed that m6A modification enhanced the back-splicing of pre-ZMYM4 to increase hsa_circ_0011536 expression in A549 and NCI-H1299 cells. Moreover, hsa-miR-576-5p was the target of hsa_circ_0011536, while transferrin receptor (TFRC) was the downstream target of hsa-miR-576-5p in A549 and NCI-H1299 cells. Furthermore, hsa_circ_0011536 elevated TFRC expression by sponging hsa-miR-576-5p in A549 and NCI-H1299 cells, identified by luciferase reporter assay. In addition, hsa_circ_0011536 induced ferroptosis through hsa-miR-576-5p in A549 and NCI-H1299 cells. Therefore, this study revealed that m6A-induced hsa_circ_0011536 elevated TFRC expression to induce ferroptosis by sponging hsa-miR-576-5p in NSCLC. These results might provide novel therapeutic targets for NSCLC treatment.

This study aimed to evaluate synergistic effects and molecular mechanisms of the histone deacetylase inhibitor chidamide combined with the BCL-2 inhibitor venetoclax in diffuse large B-cell lymphoma (DLBCL) cell lines. Human DLBCL cell lines (U2932, SUDHL-4) were cultured in vitro and treated with chidamide and venetoclax. Cell proliferation inhibition rates were measured using the CCK-8 assay, and IC50 values were calculated. Cells were also treated with a 5:1 combination of chidamide and venetoclax, along with p53 or p21 siRNA. Cell viability, HDAC activity, apoptosis, cell cycle, the amount of p53 and p21 proteins, and BCL-2-BIM binding were analyzed via CCK-8, enzyme activity assays, the Caspase 3/7 Activity Apoptosis Assay Kit, flow cytometry, RT-qPCR, western blot, and co-IP. The binding of p53 and p21 was verified by dual-luciferase reporter assay and chromatin immunoprecipitation. Chidamide and venetoclax exhibited dose- and time-dependent anti-proliferative effects in U2932 and SUDHL-4 cells, with IC50 values of 3.54 μM (chidamide) and 0.67 μM (venetoclax) in the SUDHL-4 cell line and 5.6 μM (chidamide) and 0.91 μM (venetoclax) in the U2932 cell line. Combination treatment significantly enhanced HDAC inhibition, histone H3/H4 acetylation, and p53 expression, leading to increased cell apoptosis. p53 knockdown partially reversed these effects and increased BCL-2/BIM complex formation. The combination also upregulated p53 expression to increase p21 expression, inducing G1/S phase arrest, which was partially reversed by p21 knockdown. To conclude, the chidamide-venetoclax combination synergistically activates the p53-p21 signaling pathway, leading to cell cycle arrest and apoptosis, representing a potential therapeutic strategy for DLBCL.

Gastric cancer (GC) is a prevalent gastrointestinal malignancy, with metabolic reprogramming, particularly glycolysis, playing a critical role in cancer cell stemness. However, the interaction between glycolysis and GC prognosis, along with its underlying mechanisms, remains poorly understood. This study aimed to systematically analyze the prognostic significance of glycolysis in GC and explore its functional impact. A glycolysis-related gene score was constructed using bioinformatics to assess glycolysis levels based on differentially expressed genes between GC and normal tissues. A nomogram model was developed to predict clinical prognosis, and the functional phenotypes of GC cell lines cultured under high and low glucose conditions were evaluated using metabolite detection and extracellular acidification rate (ECAR) measurements. Enrichment analyses identified key signaling pathways, which were further validated by western blot. Results showed that elevated glycolysis was associated with larger tumor size and poorer prognosis in GC patients. The nomogram demonstrated strong predictive accuracy. High glucose culture promoted glucose consumption, lactate production, ATP generation, and ECAR, enhancing epithelial-mesenchymal transition and malignant progression via the PI3K/AKT pathway. In conclusion, high glycolysis is linked to poor prognosis in GC and drives metastasis and stemness through the PI3K/AKT signaling pathway, highlighting its potential as a prognostic marker and therapeutic target.

Brain metastases (BM) are a common and challenging complication of advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of the combination of temozolomide (TMZ) and anlotinib as a second-line treatment in advanced NSCLC patients with BM. Clinical data of advanced NSCLC patients with BM between January 2020 and December 2023 were retrospectively reviewed and analyzed. All patients received TMZ combined with anlotinib as a second-line treatment. The primary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). A total of 52 patients were enrolled, with 20 females and 32 males. The median PFS and OS were 5.0 months and 10.0 months. The ORR and DCR were 25% and 65%, respectively. Subgroup analysis demonstrated that patients who developed AEs such as hypertension, proteinuria, and hand-foot syndrome, as well as those with a favorable diagnosis-specified graded prognosis assessment score, had better efficacy outcomes, indicating these features may help to identify the priority population for this regimen. Common AEs, including hematological toxicity, fatigue, and hypertension, were generally manageable with dose adjustments and supportive care. TMZ combined with anlotinib could be a safe and effective second-line treatment option for advanced NSCLC patients with BM. Prospective trials are warranted to confirm these findings and optimize the treatment strategy.

Growing evidence indicates that ferroptosis is pivotal in the development and progression of ovarian cancer (OC). However, the function of EGLN2 in OC remains unclear. In this study, we observed that EGLN2 is expressed at low levels in OC tissues and is associated with a favorable prognosis in early-stage patients based on data from TCGA and GTEx public databases. Compared with those in normal ovarian epithelial cell lines, EGLN2 mRNA and protein levels were significantly lower in OC cell lines. In vitro functional experiments revealed that EGLN2 overexpression reduced proliferation, increased the intracellular levels of iron ions, reactive oxygen species, lipid peroxidation, and mitochondrial oxidative phosphorylation, and inhibited the Warburg effect. Mechanistically, EGLN2 inhibited the expression of HIF-1α, which binds to the promoter of ceruloplasmin (CP), reducing the proliferation of and inducing ferroptosis in OC cells. A subcutaneous xenograft model in nude mice demonstrated that EGLN2 overexpression inhibited HIF-1α, promoted ferroptosis, and inhibited OC cell growth. In summary, EGLN2 suppressed CP transcription and increased ferroptosis in OC cells. These findings provide new insights into OC development and open avenues for innovative therapies.

The aim of the retrospective cohort study was to evaluate the overall survival of patients with castration-resistant prostate cancer and osteoblastic bone metastases without visceral metastases treated with 223Radium dichloride (223Ra). The cohort included 55 patients aged 48 to 86, with a median age of 71. Overall survival from the first administered cycle (from 7/2015 to 7/2019) was evaluated in 10/2024. The median overall survival was, despite a smaller cohort, 16.27 months (CI: 11.87-20.98 months), comparable to other large real-world studies. Asymptomatic or mildly symptomatic patients with good performance status (ECOG 0-1) at the start of therapy had a significantly higher median survival than more symptomatic patients with ECOG 2 and 3 (22.42 vs. 8.06 and 3.28 months). The number of completed cycles of 223Ra was inversely proportional to the patients' performance status (ECOG) - Kendall's Tau-c = -0.625; p<0.0001. Previous treatment with chemotherapy (41.2 % of patients) was associated with significantly worse survival on multivariable analysis. A decrease of serum PSA by more than 50% (12.7% of patients) was significantly associated with longer survival (31 months; p=0.0043). Severe (Grade 3) anemia, leukopenia, and thrombocytopenia occurred in only 9.1%, 3.6%, and 3.6% of patients. Earlier indication of 223Ra dichloride therapy in asymptomatic or mildly symptomatic patients with good performance status (ECOG 0-1) and without prior chemotherapy improved survival in our cohort. The decrease in serum PSA during treatment was a good prognostic factor associated with longer survival.