Hepatocellular carcinoma (HCC) is a common malignancy with high risk of recurrence and metastasis. Growing evidences reveal that aberrant mRNA splicing represents a crucial molecular characteristic of cancer, which produces numerous and complex transcript variants to drive cancer development and progression. Here, we identified the splicing factor U2AF2 as a promising oncogenic biomarker in HCC, and subsequently explored its biological role and mechanism. Through bioinformatics analysis and clinical verification, U2AF2 was found to be significantly elevated in HCC, showing a strong correlation with the pathological grade and patient outcomes. Subsequent investigations demonstrated that U2AF2 promoted HCC growth and metastasis both in vitro and in vivo. Mechanically, U2AF2 exerted its oncogenic functions by cooperating with SRSF1 to bind to the pre-mRNA of CCND1(Cyclin D1) and facilitate the generation of CCND1b isoform. Moreover, U2AF2 could potentially be utilized for the prediction of chemo-responsiveness. Its depletion sensitized HCC cells to Doxorubicin, a first-line chemotherapy agent for advanced HCC patients. Altogether, this study deepens our understanding of U2AF2 in mRNA splicing and provides a potential therapeutic target for HCC.

Traditional differential gene identification relies on bulk analysis, which lacks spatial resolution and limits the detection of spatially variable genes due to intratumoral heterogeneity. Spatial transcriptomics addresses this, but high costs reduce sample sizes and statistical power.

Gastric cancer (GC) remains one of the most formidable threats to human health with limited therapeutic options. Sulforaphane (SFN), a natural isothiocyanate, exhibits antitumor activity; however, its molecular mechanisms of action in GC remain unclear.

Breast cancer (BC) is the leading malignancy affecting women globally, characterized by significant heterogeneity. Therefore, our objective was to explore potential targets within the context of intra-tumor heterogeneity (ITH) to modulate the response of tumor-associated macrophages (TAMs) to treatment in BC patients. The TCGA database was used to integrate and analyze human BC samples, from which the ITH score was extracted to identify genetic differences. Using non-negative matrix factorization clustering analysis, we successfully identified two distinct molecular subtypes, referred to as C1 and C2. Notably, subtype C1 exhibited a significantly more favorable prognosis compared with subtype C2. Further investigation of immune cell infiltration using the CIBERSORT algorithm revealed a significant correlation between both subtypes and the infiltration of TAMs. Additionally, we identified SPIB as a key factor influencing TAM infiltration within the model. Notably, SPIB is expressed at low levels in BC and is associated with an unfavorable prognosis for patients. Interestingly, overexpression of SPIB led to increased infiltration of M1 macrophages. In conclusion, this study sheds light on the characteristics of BC and immune cell infiltration within its microenvironment. SPIB emerges as a promising therapeutic candidate, with potential to modulate the immunosuppressive nature of the BC microenvironment and improve patient outcomes.

Helicobacter pylori (H. pylori) infection promotes the progression of gastric cancer. The purpose of this study is to investigate the effects of H. pylori infection on gastric cancer and the underlying mechanisms. mRNA levels were determined by reverse transcription quantitative PCR (RT-qPCR). Protein expression was detected by Western blot. Cell viability was detected by Cell Counting Kit-8 assay. Cell proliferation was detected by colony formation assay. Cell mobility was detected by transwell assay. The co-localization of NEDD8 activating enzyme E1 subunit 1 (NAE1) and transferrin receptor 1 (TFR1) was determined by fluorescence in situ hybridization (FISH) assay. TFR1 neddylation was determined using in vitro neddylation assay. H. pylori infection contributed to the proliferation, migration, and invasion of gastric cancer. Moreover, H. pylori infection inhibited erastin-induced ferroptosis of gastric cancer cells. H. pylori infection downregulated NAE1, which promoted the neddylation and protein stability of TFR1. Intriguingly, overexpressed NAE1 inhibited the metastasis as well as promoted the ferroptosis of gastric cancer. H. pylori infection mediates malignant behaviors of gastric cancer via inactivating NAE1/TFR1 signaling. Therefore, targeting NAE1/TFR1 signaling may provide a novel strategy for gastric cancer.

Prostate cancer (PRAD) progression varies significantly among patients, with metabolic reprogramming linked to oncogenesis and immune response. However, the prognostic and immune-related roles of metabolic reprogramming-related genes (MRGs) in PRAD remain unclear. PRAD transcriptomic, mutation, and clinical data from TCGA were analyzed. WGCNA identified PRAD-associated gene modules. NMF clustering stratified patients into two molecular subgroups. Prognostic MRGs were screened via univariate Cox and LASSO regression. A gene-based prognostic model was established and validated using ROC, PCA, and Kaplan-Meier analyses. A clinical-variable nomogram predicted survival, with external validation via GEO data set GSE70770. Immune traits of subtypes/risk groups were assessed via ESTIMATE, CIBERSORT, and ssGSEA. Drug sensitivity and gene expression (qRT-PCR) were evaluated. Two metabolic subtypes with distinct survival and immune patterns were identified. A four-gene signature (AKR1C2, PITPNM3, PLA2G5, UCK2) formed a prognostic model. Risk stratification revealed groups with divergent survival rates. High-risk patients exhibited poorer outcomes, reduced immune infiltration, and altered drug sensitivity. The MRG prognostic model stratifies PRAD patients by survival and immune landscape, aiding precision immunotherapy and drug discovery.

The chloride intracellular channels (CLICs) engage in cancer pathogenesis and have been considered various cancer biomarkers and therapeutic targets. Preliminary research suggests CLICs may be important players in head and neck squamous cell carcinoma (HNSCC). There is a need for reliable HNSCC biomarkers besides well-known HPV and PD-L1.

While lung cancer remains a lethal disease despite treatment advances, some parasitic infections can demonstrate cancer-modulating roles and exhibit anti-tumor effects. The emergence of hydatid cysts as a potential anti-cancer treatment has sparked optimism for the development of more successful therapies. This research examines the effect of hydatic cysts on the growth and proliferation of lung tumor cells, as well as the underlying molecular mechanisms involved. The laminated layer (LL) of the hydatid cyst antigens was administered to lung cancer cells with varying dosages and durations. The MTT assay was applied to evaluate cell viability. After exposure to different concentrations of LL antigens, the apoptosis, necrosis, cell cycle, and intracellular reactive oxygen species (ROS) of the cell culture were measured using flow cytometry. The expression levels of SOX-9, β-catenin, CD133, and CD44 genes were assessed using Real-Time PCR. Treating A549 cells with varying concentrations of LL antigens resulted in a decrease in viable cells, which depended on both time and dosage. Treatment with cysts led to apoptosis induction and a reduction in necrosis percentage in a dose-dependent manner. The induction of apoptosis correlated with elevated ROS production and a notable decrease in the expression of invasion-related genes (β-catenin, CD133, and CD44) (P < 0.05). However, this reduction in expression was not statistically significant for SOX-9. Exposing lung cancer cells to precise amounts of crude LL antigens resulted in cell death, apoptosis, increased intracellular ROS levels, and reduced expression of genes linked to cancer cell growth and invasion. These results lay the groundwork for further exploring purified Echinococcus granulosus parasite antigens as potential drug targets in cancer treatment.

β2-integrins are a family of adhesion proteins expressed in immune cells that play multiple roles in anti-tumor immunity. β2-integrins regulate tumor infiltration of anti-tumorigenic immune cells such as cytotoxic CD8 + T cells and NK cells. However, they also regulate the activity of myeloid cells, such as macrophages, which can have both anti- and pro-tumorigenic properties. The role of β2-integrins in urothelial cancer remains poorly understood. Here, we have investigated the role of different β2-integrins, and their cytoplasmic regulators, in urothelial cancer, by utilizing RNA expression data. We found that ITGAL (encoding for CD11a) and FERMT3 (encoding for the integrin regulator kindlin-3) have a positive correlation with patient survival. EcoTyper analysis revealed increased infiltration of CD8 + T cells and NK cells in ITGAL high samples, but ITGAL or FERMT3 expression did not correlate with response to immunotherapy. In contrast, ITGAM and ITGAX (which encode for myeloid markers CD11b and CD11c) and FLNA (encoding for the integrin regulator filamin A) correlated with poor survival and reduced responsiveness to immunotherapy and critically regulate the tumor myeloid immune landscape (M1/M2 macrophages, cDC1 dendritic cells). Therefore, β2-integrins may be explored in the future as biomarkers to differentiate urothelial cancer patients with different immune landscapes, responding differently to therapy.

The incidence of colorectal cancer in young adults (age of diagnosis <50 years) has been rapidly increasing. Although ∼20% of early-onset colorectal cancer (EOCRC) cases are due to germline mutations, the etiology of the majority of EOCRC cases remains poorly understood. Nongenetic factors such as environmental exposure and lifestyle changes are likely to have a direct link to the increased incidence of sporadic EOCRC. We hypothesize that such factors may be observable as alterations in the epigenome, microbiome, and immunome. We characterized the DNA methylation (DNAm) signature and measured DNAm age in EOCRC by using The Cancer Genome Atlas (TCGA). Furthermore, we carefully identified intratumoral microbes from TCGA and the Oncology Research Information Exchange Network datasets and then related the microbes to deconvolved immune cell abundances in EOCRC. We observed that the DNAm age in the EOCRC cohort was 12 years older when compared with the average-onset colorectal cancer (AOCRC) cohort, using three different epigenetic clocks. Differentially methylated sites associated with gene expression include cAMP-responsive element binding protein signaling in neurons, G protein-coupled receptor signaling, phagosome formation, and S100 family signaling. These differences were validated in the gene expression data from TCGA and the Oncology Research Information Exchange Network. When comparing the intratumoral microbes between EOCRC and AOCRC, no consistent differences were observed. Interestingly, the most abundant microbes interacted with the immune systems differently between the EOCRC and AOCRC tumors, characterized by more and larger positive correlations in EOCRC. These data suggest that epigenetic modulation and accelerated aging may play a key role in the development of EOCRC.

Globally, millions of cancer cases are diagnosed annually and mortality rates continue to rise with breast (BC), colorectal (CRC) and prostate (PC) cancer among the most prevalent. Race and ethnic disparities in cancer outcomes have been well-documented; however, the underlying factors contributing to these disparities are currently unknown.

The RAS pathway and developmental stage are known to influence leukemic cell proliferation and drug resistance. However, their impact on the prognosis of acute myeloid leukemia (AML) patients, particularly post-allo-HSCT, remains unclear. This study aimed to explore the effects of RAS-pathway mutations and developmental stage on the outcomes of AML patients who received allo-HSCT. A total of 364 consecutive adult AML patients who underwent their first allo-HSCT with myeloablative conditioning were enrolled in this study. The primary endpoint of this study was the cumulative incidence of relapse (CIR) and secondary endpoints were OS and leukemia-free survival (LFS). RAS-pathway mutations were detected in 57 patients (15.7%). Subgroup analysis revealed opposite outcomes: RAS-pathway mutations were associated with a higher cumulative incidence of relapse (CIR) (38.6% vs. 14.8%, P = 0.016) in the primitive AML subgroup and a lower CIR (3.4% vs. 26.8%, P = 0.013) and better leukemia-free survival (LFS) (93.1% vs. 66.9%, P = 0.013) in the monocytic subgroup, compared with AML patients without RAS-pathway mutations. Subgroup multivariable analyses in the primitive subgroup revealed that patients with RAS-pathway mutations had a higher CIR (hazard ratio [HR] = 2.55, 95% confidence interval [CI]: 1.21-5.40). Meanwhile, subgroup multivariable analyses in the monocytic subgroup showed that patients with RAS-pathway mutations exhibited a significantly improved LFS (HR = 0.23, 95% CI: 0.06-0.96). In summary, the prognosis of AML patients with RAS-pathway mutations who received allo-HSCT can be significantly influenced by the developmental stage at which the mutation occurs.

Diffuse Large B-Cell Lymphoma (DLBCL) exhibits significant biological heterogeneity, leading to diverse clinical outcomes. Ubiquitination, a post-translational modification process, plays a crucial regulatory role in tumor development and progression. The prognostic profile of ubiquitinated genes in DLBCL needs to be explored. We analyzed three datasets (GSE181063, GSE56315, and GSE10846) to identify ubiquitination-related survival-associated differentially expressed genes (DEGs) in DLBCL. We constructed a ubiquitination-based prognostic signature and calculated risk scores. Using R software, we investigated relationships between the identified DEGs, high- and low-risk groups, immune microenvironment, drug sensitivity, and single-cell composition. Three key ubiquitination-related survival-associated DEGs were identified: Cell Division Cycle 34 (CDC34), Fizzy-related protein homolog 1 (FZR1), and OTU Deubiquitinase with Linear Linkage Specificity (OTULIN). Elevated expression of CDC34 and FZR1, coupled with low expression of OTULIN, correlated with poor prognosis in DLBCL. These genes correlation with endocytosis-related mechanisms, T-cell, and drugs sensitive. Significant differences in immune scores and concentration for Boehringer Ingelheim compound 2536 and Osimertinib were observed between high- and low-risk groups. This study establishes a novel ubiquitination-based prognostic signature for DLBCL, offering insights into potential therapeutic targets and strategies for personalized treatment approaches.

The incidence and prognosis of high-grade gliomas differ according to histopathological and molecular features. The WHO 2021 CNS classification emphasized IDH status, but historical cohorts often lacked systematic molecular profiling.

Stomach adenocarcinoma is a major contributor to worldwide mortality and significantly impacts life expectancy. The main objective of the current study was to identify a prognostic biomarker for stomach adenocarcinoma to advance translational medicine and improve patient outcomes.

The present study investigated the role of YWHAH in colorectal cancer (CRC) progression, focusing on its regulation of autophagy via the MAPK/ERK signaling pathway and subsequent effects on cell migration and invasion. Clinical sample analysis revealed that YWHAH was highly expressed in CRC tissues, associating with poor differentiation, advanced TNM stage, lymph node metastasis, vascular invasion and unfavorable prognosis. In vitro experiments showed that YWHAH overexpression promoted proliferation, and epithelial‑mesenchymal transition of CRC cells, while inhibiting apoptosis. Conversely, YWHAH knockdown exerted opposite effects. Autophagy assays demonstrated that YWHAH knockdown enhanced autophagy by upregulating autophagy related 7 and LC3II/I and downregulating P62, whereas overexpression suppressed autophagy. Mechanistically, YWHAH negatively regulated the MAPK/ERK pathway [reducing phosphorylated (p)‑ERK1/2 and p‑ELK‑1 levels] to inhibit autophagy. The ERK inhibitor PD98059 reversed autophagy activation by YWHAH knockdown, while the ERK agonist U‑46619 reversed autophagy suppression by YWHAH overexpression. Additionally, the autophagy inhibitor 3‑methyladenine abrogated the inhibitory effects of YWHAH knockdown on migration and invasion, and the autophagy inducer rapamycin reversed the promoting effects of YWHAH overexpression. In vivo, nude mouse xenograft models confirmed that YWHAH inhibited autophagy via the MAPK/ERK pathway to accelerate tumor growth. These findings underscore the role of YWHAH as a critical regulator of CRC progression and suggest it as a potential therapeutic target. Interventions targeting YWHAH or its downstream factors may provide innovative approaches for treating CRC, particularly by modulating autophagy to inhibit tumor growth and metastasis.

Liquid‑liquid phase separation (LLPS) contributes to multiple cellular bioprocesses; however, its clinicopathological relevance to oral squamous cell carcinoma (OSCC) remains largely unexplored. In the present study an integrative multi‑omics analysis investigating the prognostic value and molecular functions of LLPS‑related genes (LLPSRGs) in OSCC was conducted by leveraging transcriptomics and clinical data from 302 cases in The Cancer Genome Atlas database and LLPSRGs. A total of two prognostically distinct molecular subtypes were stratified by unsupervised clustering analysis, and a robust prognostic signature comprising seven key LLPSRGs was developed through LASSO regression and multivariate Cox analysis. Functional enrichment analysis highlighted the involvement of this signature in epithelial‑mesenchymal transition (EMT), with PHLDB2 emerging as a core regulator. Notably, the PHLDB2 protein underwent LLPS and formed droplet condensates both outside and in OSCC cells. Moreover, functional experiments revealed that PHLDB2 depletion attenuated the malignant biological behavior of OSCC cells, including cell proliferation, stemness, invasion and migration, and PHLDB2 promoted OSCC progression by regulating the PI3K‑Akt signaling pathway and PIK3CA expression. Retrospective clinical cohort and public dataset analyses validated that high expression of PHLDB2 was significantly associated with lymph node metastasis, higher pathological grade and reduced survival in patients with OSCC. Collectively, the present study established an LLPS‑based prognostic signature for OSCC, and revealed that phase separation of PHLDB2 may drive OSCC progression through regulating EMT and PIK3CA.

Following the publication of the above paper, a potential problem regarding the presentation of the co‑localization experiments shown in Fig. 5A and C was brought to the Editor's attention by a concerned reader. Specifically, the Flotillin/gp91 co‑localization panels (Fig. 5A) appeared to be unexpectedly similar to the Flotillin/p22 panels (Fig. 5C), even though, according to the Materials and methods section, the different antibody treatments that were reported might have precluded the possibility of these images looking so similar. The authors were contacted by the Editorial Office to offer an explanation for this potential anomaly in the presentation of the data in this paper (or to clarify how the experiments had been performed), although up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [International Journal of Oncology 37: 1483‑1493, 2010; DOI: 10.3892/ijo_00000801].

Extracellular matrix (ECM) proteins are key non‑cellular components of the tumor microenvironment and include structural and non‑structural proteins. POSTN belongs to a family of non‑structural matrix cell proteins first identified in bone and periodontal ligaments. POSTN exerts its multiple effects mainly through specific binding to other ECM proteins, growth factors and cytokines. Physiologically, POSTN is rarely expressed in adult tissues, except in the periosteum and some collagen‑rich connective tissues, such as periodontal ligaments and heart valves, but is highly expressed during inflammation, tissue repair, wound healing and malignant transformation. POSTN carries out an important role in tumor development. The present review summarizes the multiple roles of POSTN in tumorigenesis and development. First, the molecular structure of POSTN and its physiological and pathological expression, especially in known tumors is reviewed. Second, the manner in which POSTN affects tumor cells through relevant cancer hallmarks is discussed. Finally, the molecular mechanisms underlying the promotion of cancer by POSTN from the perspective of the TME is summarized.

Leucine‑rich repeat‑containing protein 59 (LRRC59), a 244‑amino‑acid endoplasmic reticulum membrane protein, is implicated in the tumorigenesis of multiple malignancies. However, its functional significance in colorectal cancer (CRC) remains poorly understood. In the present study, LRRC59 expression in CRC tissues was evaluated using immunohistochemistry and western blotting. Colony formation, Cell Counting Kit‑8, wound healing and Transwell assays, in in vivo xenograft models, were used to evaluate the effect of LRRC59 on CRC progression. Apoptosis was analyzed using flow cytometry and western blotting. The interaction between LRRC59 and the protein kinase RNA‑like endoplasmic reticulum kinase (PERK) pathway was verified using the starBase database and western blotting. It was found that LRRC59 expression was significantly higher in CRC tissues than in normal tissues. LRRC59 knockdown in HCT116 and LoVo cells inhibited proliferation, migration and invasion and promoted apoptosis, and the PERK pathway was significantly activated. In vivo subcutaneous tumorigenesis assays corroborated these in vitro findings. Treatment with a PERK pathway‑specific inhibitor reduced the apoptosis of HCT116 and LoVo cells with LRRC59 knockdown. These findings suggest that LRRC59 is not only significantly upregulated in CRC but also mechanistically drives tumor progression by coordinating pro‑oncogenic processes, including enhanced proliferation, migration and invasion. Importantly, mechanistic evidence was provided that LRRC59 inhibits apoptosis by suppressing the PERK signaling axis, identifying this molecule a target in the development of CRC therapeutic strategies.