Hepatocellular carcinoma (HCC) is a prevalent digestive system malignancy with a poor prognosis. Previous studies suggested that elevated CD47 expression, a member of the immunoglobulin superfamily, is correlated with poor outcomes in various cancers. However, the precise mechanisms through which CD47 influences HCC progression remain unclear.

USP5, a deubiquitinating enzyme, is linked to various cancers. However, its relationship with immune infiltration and its prognostic significance in non-small-cell lung cancer (NSCLC) remains to be determined.

Urothelial carcinoma is the third most common cancer in Lynch syndrome but there is no approved screening method. Lynch syndrome cancers are characterised by high levels of microsatellite instability (MSI/MSI-H). Here, we assess the feasibility of urine MSI analysis for non-invasive urothelial carcinoma screening.

Multiple Myeloma (MM) is a malignancy characterized by an uncontrolled proliferation of malignant plasma cells in the bone marrow and remains incurable. Treatment typically consists of a multimodal approach, with glucocorticoids (GC) as a crucial treatment pillar in the diagnosis and relapsed settings. Inevitably, patients become therapy resistant, but to which component of the treatment armamentarium the tumor becomes refractory is unknown. Here we used different in cellulo models of GC resistance to gain insights into the mechanistic processes of emerging GC therapy resistance. We found that differential baseline GC responsiveness of the cells is associated with significant differences in the timing and the degree to which myeloma cell lines become resistant to GCs. We corroborated that the chemokine receptor CCR1 is a shared biomarker between MM cell lines upon the emergence of GC resistance. Significant overlap exists between pathways enriched in partial GC-resistant MM.1S cells and those enriched in relapsed patients whose treatment included GCs. In addition, enrichment analyses demonstrated that alterations in metabolism and plasma cell expression signatures are associated with decreased sensitivity to GCs. From these analyses, we validated a biomarker, fatty acid synthase (FASN), and pinpointed its pivotal role in determining the GC sensitivity of myeloma cells, offering future opportunities for enforcement of GC sensitivity and re-sensitization.

There is growing evidence that exosomes produced by bone marrow stromal cells (BMSCs) are associated with the progression of several cancers, including acute myeloid leukemia (AML), but intrinsic molecular mechanisms remain elusive. Here, we applied previous microarray analysis (GSE133276 and GSE209871) to identify differentially expressed exosomal miRNAs in BMSCs of AML patients, and candidate miR-140-3p, miR-142-5p and miR-142-3p were selected. This study aimed to investigate whether BMSCs affects AML progression are mediated by the candidates, and to explore regulatory mechanisms. The levels of the candidates were examined in bone marrow and BMSCs from AML patients, and exosomes from BMSCs of normal subjects and AML cells by qRT-PCR. Cell proliferation and apoptosis of AML cells co-cultured with BMSCs were detected through CCK-8, colony formation, flow cytometry, and Caspase-3 activity assays with manipulation of the candidate miRNAs expression. RNA pull-down and luciferase reporter assays to identify the downstream target mRNAs of the miRNAs. We confirmed that miR-140-3p, miR-142-5p and miR-142-3p levels were downregulated in bone marrow and BMSCs of AML patients, and were significantly enriched in exosomes of BMSCs but not AML cells. BMSCs co-cultured with AML cells could transfer these miRNAs into AML cells, and suppressed the proliferative potential and promoted the apoptotic behavior of AML cells. Furthermore, miR-140-3p agomir in BMSCs exacerbated the effects of the co-culture system on the AML cell proliferation and apoptosis, which were attenuated by miR-140-3p antagomir. In contrast, co-culture data showed that miR-142-5p and miR-142-3p had no significant effect on cell proliferation and apoptosis. Moreover, SUZ12 polycomb repressive complex 2 subunit (SUZ12) was directly targeted by miR-140-3p, overexpression or inhibition of SUZ12 in AML cells partially counteracted miR-140-3p agomir or antagomir-mediated cellular effects, respectively. Our study suggested that the BMSCs-derived exosomal miR-140-3p, rather than miR-142-5p and miR-142-3p, has a regulatory effect on the growth and apoptosis of AML cells by targeting SUZ12.

KRASG12C mutation, which is observed in ∼14 % of lung adenocarcinoma cases, has been established as a pivotal therapeutic target in precision oncology approaches. Herein, a novel series of 1,2-dihydropyrido[2,3-d]pyrimidine-6‑carbonitrile derivatives was developed as KRASG12C inhibitors. One representative compound 8 t exhibited remarkable antiproliferative activity against KRASG12C-mutant non-small-cell lung cancer (NSCLC) cell H358 with an IC50 value of 7.6 nM. It also displayed optimized drug-like properties, including enhanced liver microsomal stability (human, T1/2 = 188.2 min), favorable pharmacokinetic properties [oral bioavailability (F%) = 114.5 %], and minimal hERG liability (IC50 > 30 μM). Notably, compound 8 t achieved significant tumor growth inhibition (TGI = 167.9 %) in H358 xenograft models at a dosage of 30 mg/kg qd without significant weight loss, highlighting its therapeutic potential and safety margin. This study characterizes novel candidate compound 8 t, which may advance the development of targeted therapies against KRASG12C-mutant NSCLC.

Neoadjuvant therapy (NAT) is the standard of care for most HER2-positive early breast cancer (BC). However, 25 to 50% of patients fail to achieve a pathological complete response (pCR). This study evaluates the CE/IVD MammaTyper® kit (Cerca Biotech) as a predictor of response in this setting.

DNA damage response (DDR) is a complex network of biological pathways, maintaining eukaryotic genetic stability and frequently altered in cancer cells. Aberrant DDR regulation could be a double-edge sword in cancer: DDR defects could lead to genetic instability driving the acquisition of cancer mutations, while alternative DDR pathways could provide the survival benefits for genetic-unstable cancer cells. Targeting DDR defects in cancer, most noticeably through PARP inhibitors, exhibit impressive clinical efficacy in multiple cancer types. Here, we update recent progress concerning DDR and its inhibitors in pediatric cancers, from molecular mechanism to clinical practice.

Bortezomib (BTZ) containing regimens induces significant antitumor response in multiple myeloma (MM) and are considered as the first-line treatment. However, resistance is still one of the unsolved problems. This study aims to explore the mechanism underlying BTZ resistance in MM.

Cancers that do not respond to immunotherapy typically harbor a non-T cell-inflamed tumor microenvironment (TME), characterized by the absence of type I/II interferon signaling and CD8+ T cell infiltration. We previously reported IDH1 somatic mutations were enriched in this phenotype across histologies. Mutant IDH1 (mIDH1) drives immune exclusion via metabolic reprogramming of the TME, and preclinical models show that IDH inhibition can restore anti-tumor immunity. We conducted a Phase II study assessing the preliminary activity of ivosidenib, an IDH1 inhibitor, plus nivolumab, an anti-PD1 antibody, in patients with mIDH1 advanced solid tumors (NCT04056910).

Lung squamous cell carcinoma (LUSC) remains an aggressive malignancy with limited therapeutic options and poor prognosis. Understanding the molecular drivers of LUSC pathogenesis is crucial for developing novel interventions. This study investigates the functional significance and mechanistic basis of long non-coding RNA LINC00885 in LUSC progression. We employed integrated methodologies including bioinformatic analysis, clinical specimen validation, in vitro functional assays (EdU incorporation, colony formation, Transwell migration/invasion), molecular profiling (qPCR, immunoblotting, northern blot, fluorescence in situ hybridization, subcellular fractionation), mechanistic investigations (chromatin isolation by RNA purification, luciferase reporter assays), and in vivo xenograft modeling. LINC00885 was significantly upregulated in LUSC clinical tissues and cell lines. Genetic depletion of LINC00885 suppressed malignant phenotypes including cellular proliferation, migration, invasion, and epithelial-mesenchymal transition. Mechanistically, LINC00885 directly bound and repressed tumor-suppressive miR-654-3p, which targeted stem-loop binding protein (SLBP). LINC00885 activated PI3K/Akt signaling through SLBP upregulation, and either SLBP overexpression or miR-654-3p depletion rescued the tumor-suppressive effects of LINC00885 knockdown. Xenograft models confirmed LINC00885 silencing significantly inhibited tumor growth in vivo. LINC00885 promotes LUSC progression via the miR-654-3p/SLBP/PI3K/Akt signaling axis.

Triple-negative breast cancer (TNBC) is notorious for its rapid progression, tendency to metastasize, high recurrence rates, dismal outcomes, and limited treatment options, underscoring the urgent need to uncover new biomarkers and molecular pathways to enhance diagnosis, prognosis, and therapeutic strategies. Metabolic reprogramming continues to play a role throughout the life cycle of cancer, evolving and adapting. In this study, we aimed to identify specific genes associated with metabolic reprogramming in TNBC, which can potentially become unique biomarkers of this cancer. TNBC datasets retrieved from the Gene Expression Omnibus were employed to pinpoint genes exhibiting altered expression linked to tumor metabolic reprogramming. Key genes were accurately screened through machine learning algorithms, and then externally verified using the TBNC dataset based on the Cancer Genome Atlas database. Finally, immunohistochemical methods were used to clinically confirm the differential expression and trends of these key genes. Our analysis accurately identified four genes-CLEC7A, IRS1, RSPO3, and ALB-that are closely correlated with the metabolic reprogramming characteristics of cancer, and could be regarded as innovative biomarkers for TNBC. This opens a new avenue for further investigation into the mechanisms of metabolic reprogramming in TNBC and new treatment strategies.

Cell-to-cell communication through ligand-receptor (LR) interactions can fundamentally shape the tumor microenvironment and immune responses, but the full spectrum of these interactions in anti-PD-1 therapy remains unexplored. We developed a predictive model for anti-PD-1 therapy responses incorporating 2,705 LR pairs across 121 melanoma samples. Using a random forest classifier, our model achieved robust accuracy in the training and test datasets as well as in two independent external validation cohorts. Feature importance analysis revealed nine key LR pairs with substantial predictive power, including both known immune checkpoint molecules and novel interaction pairs. The genes comprising these top-ranking pairs were significantly enriched in tumor-related pathways, particularly MAPK and PI3K/AKT signaling pathways. Importantly, our systematic LR profiling approach identified previously uncharacterized ligand-receptor interactions that may represent alternative therapeutic targets beyond the established PD-1/PD-L1 axis. These findings demonstrate the clinical utility of integrated LR expression analysis for predicting anti-PD-1 therapy responses and reveal potential novel biomarkers and combination therapy targets that could expand treatment options for immunotherapy-resistant patients.

Colon adenocarcinoma (COAD) is highly malignant tumor in the gastrointestinal tract, and reliable biomarkers for predicting its prognosis are remain lacking. MIER Family Member 2 (MIER2) has been implicated in tumor biology, yet its role in COAD remains unclear. MIER2 expression in COAD was analyzed using TCGA and UALCAN databases. Survival analysis, Cox regression, and nomogram construction were performed to evaluate its prognostic value. Functional enrichment analysis was conducted via LinkedOmics. Immune infiltration was assessed using ESTIMATE and CIBERSORT algorithms. Additionally, the effect of MIER2knockdown on the proliferation, and migration of SW480 cell was evaluated. The expression of MIER2 was significantly higher in COAD tissues and associated with a poorer OS, DSS and PFI. Multivariate analysis confirmed MIER2 as an independent prognostic factor. Co-expressed gene analysis revealed enrichment in immune-related pathways, including type I interferon signaling and macrophage activation. In addition, MIER2 expression was associated with altered immune infiltration. MIER2 knockdown suppressed SW480 cell proliferation and migration, and RNA-seq further indicated that this might be related to the intrinsic apoptotic signaling pathway. High expression of MIER2 is associated with poor prognosis and immune cell infiltration, and it serve as a novel prognostic biomarker and potential therapeutic target for COAD.

Epigenetic research, particularly involving m6A RNA methylation-a dynamic and reversible posttranscriptional modification-has increasingly demonstrated its critical involvement in cancer pathogenesis. Although the m6A demethylase FTO is implicated in breast cancer (BC), its specific regulatory mechanisms against triple-negative breast cancer (TNBC) has not been clearly defined. Quantitative PCR (qPCR) was used to compare m6A regulatory enzyme expression in TNBC patient tissues with that in normal breast tissues, identifying FTO as the most differentially expressed enzyme. Two randomly selected TNBC/normal tissue pairs were subjected to methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Integrated analysis utilizing the SRAMP and RMBase databases predicted potential FTO target genes. Transcriptome sequencing of FTO-overexpressing TNBC cell lines identified downstream pathways. Dual-luciferase reporter assays and MeRIP-qPCR validated the functional role of FTO and its target, NFKBIE, and their regulatory interaction in TNBC. Compared with normal samples, clinical samples from TNBC patients presented significantly decreased FTO expression (p < 0.05) and correspondingly elevated global m6A levels. MeRIP-Seq confirmed substantial differences in m6A methylation (R = 0.23, p < 0.05). Bioinformatics and transcriptome analyses identified NFKBIE as the primary FTO target. Dual-luciferase assays demonstrated that FTO overexpression specifically modulated wild-type (WT), but not mutant (MT), NFKBIE promoter activity (p < 0.05). MeRIP-qPCR verified the FTO-mediated reduction in m6A methylation at three specific NFKBIE sites (p < 0.05). Functional assays (CCK-8, Transwell invasion/migration, and scratch wound healing) indicated that FTO overexpression significantly enhanced TNBC cell proliferation and motility; these oncogenic phenotypes were partially rescued by concurrent NFKBIE overexpression. FTO regulates NFKBIE expression via m6A-dependent demethylation, establishing a pivotal FTO-NFKBIE regulatory axis that drives TNBC progression. FTO overexpression promotes TNBC cell proliferation, migration, and invasion, effects that are partially reversible through NFKBIE restoration.

Endometrial cancer (EC) represents the most prevalent gynecologic malignancy. We probed the mechanism of long noncoding RNA activated by DNA damage (lncRNA NORAD) regulating ferroptosis in EC cells (ECCs) by modifying glutathione peroxidase 4 (GPX4) through N6 methyladenosine (m6A) methylation.

Actin-like protein 6A (ACTL6A) is thought to be associated with the survival and prognosis of patients with a variety of human cancers. This study investigates the effect of ACTL6A knockdown on ESCC radiosensitivity and explores molecular mechanisms that may enhance radiotherapy efficacy. The ACTL6A expression level was increased in esophageal squamous carcinoma cells after radiation irradiation. The protein expression level of ACTL6A in tumor tissue samples of clinical esophageal squamous cell carcinoma patients was analyzed by immunohistochemistry, and it was found that the prognosis of the high expression group was worse than that of the low expression group. Further knocking down the ACTL6A gene in esophageal squamous cell carcinoma cells, it was found that ACTL6A could regulate the proliferation, migration, invasion, DNA damage repair, cell cycle, and apoptosis of esophageal squamous cell carcinoma cells, which further affected the radiosensitivity of esophageal squamous cell carcinoma cells. Through functional enrichment analysis of gene set enrichment and validation of the mechanism using the Wnt pathway inhibitor XAV939, it was shown that ACTL6A is involved in the regulation of the Wnt/β-catenin signaling pathway. Knockdown of ACTL6A can inhibit the activity of this pathway, thereby increasing the radiosensitivity of esophageal squamous cell carcinoma. ACTL6A may become an important therapeutic target for esophageal squamous cell carcinoma, providing a necessary theoretical basis for future treatment strategies.

Cell division cycle-associated protein 4 (CDCA4) has the potential to indicate lung adenocarcinoma (LUAD) development, but its regulatory role in mitophagy remains unclear. This study aimed to elucidate the mitophagy regulation and therapeutic implications of CDCA4 in LUAD. CDCA4 expression was significantly elevated in LUAD clinical specimens versus paracancerous tissues and inversely correlated with mitophagy activity. Lentiviral vectors were employed to manipulate established LUAD cells, followed by treatment with chloroquine (CQ; lysosomal inhibitor) and rapamycin (autophagy inducer) in CDCA4-silenced cells. CDCA4 knockdown elevated total and mitochondrial superoxide levels, disrupted mitochondrial membrane potential, activated the PINK1/Parkin pathway, enhanced LC3-II conversion, and degraded mitochondrial membrane proteins, collectively promoting mitophagy. Silencing CDCA4 suppressed malignant phenotypes (proliferation/migration), effects reversed by CQ but exacerbated by rapamycin. Mechanistically, CDCA4 interacted with SERTAD1 and E2F1 and stabilized these proteins. The promotion of mitophagy by CDCA4 silencing was impaired by the overexpression of SERTAD1 and E2F1. LUAD cells silencing CDCA4 were injected into immunodeficient mice for in vivo verification. CDCA4-silenced xenografts exhibited suppressed tumor growth, increased apoptosis, and elevated mitophagy-related markers. This study identifies the CDCA4/SERTAD1/E2F1 complex as a pivotal mitophagy-inhibitory hub in LUAD, proposing this axis as a novel predictive and therapeutic target.

Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system. Immune checkpoint blockade (ICB) is a promising strategy for CRC treatment, but its limited efficacy poses a challenge. Bioinformatics methods were used to screen ferroptosis-related genes in CRC. Cellular biology methods investigated endothelial PAS domain protein 1 (EPAS1) impact on cellular characteristics, stemness, and ferroptosis. Finally, in vivo experiments validated EPAS1's influence on anti-PD-1 therapy efficacy. We have found that EPAS1 is a risk gene in CRC, which can inhibit the growth, invasion, and stemness of colon cancer cells both in vitro and in vivo, and promote ferroptosis. Mechanistically, caveolin 1 (CAV1) regulates the expression of von Hippel-Lindau tumor suppressor (VHL) to inhibit the ubiquitination of EPAS1, increase its stability, further enhance the expression of nuclear receptor coactivator 4 (NCOA4) and autophagy-lysosome formation, leading to cell iron overload and inducing ferroptosis. Our study confirms EPAS1 regulates ferroptosis, impacting epithelial-mesenchymal transition (EMT) and stemness in CRC cells, and highlights its role in ICB. These findings inform CRC treatment.

Previous studies suggest that granulocyte colony-stimulating factor (G-CSF) drugs may increase the risk of certain cancers, but findings remain controversial. We employed a drug-target Mendelian randomization approach to investigate the causal relationship between G-CSF and 14 cancer types. The target gene of G-CSF drugs was sourced from the DrugBank database. Expression quantitative trait loci data for the target gene (CSF3R) were obtained from the expression quantitative trait loci Gen Consortium. Genome-wide association study data for the 14 cancers were retrieved from the FinnGen dataset. A Bonferroni correction was applied for multiple testing (P < .0036). Analyses were performed using the inverse variance weighted, Mendelian randomization-Egger, weighted median, weighted mode, and simple mode methods. Heterogeneity was assessed using Cochran Q test, and sensitivity analyses were conducted to verify the reliability of the findings. Inverse variance weighted analysis revealed a significant association between genetically proxied G-CSF exposure and an increased risk of lung squamous cell carcinoma (LUSC) [odds ratio: 1.61, 95% confidence interval: 1.20-2.17, P = 1.51 × 10-3] and a potential association with estrogen receptor-negative breast cancer (odds ratio: 1.26, 95% confidence interval: 1.06-1.50, P = 7.31 × 10-3). The association with LUSC remained significant after multiple testing correction. No statistically significant associations were found with the other 12 cancers. Sensitivity analyses indicated no evidence of heterogeneity or pleiotropy. While these results suggest a potential causal role of G-CSF in the development of LUSC and possibly estrogen receptor-negative breast cancer, their clinical implications (particularly regarding long-term G-CSF use) should be interpreted with caution. Further validation in large-scale prospective studies and diverse populations is essential before any clinical recommendations can be made. Our findings highlight the need for continued investigation into the long-term safety profiles of G-CSF and may contribute to a more nuanced understanding of its risk-benefit balance in specific clinical contexts.