Castration-resistant prostate cancer (CRPC) is the advanced stage of prostate cancer (PCa) progression, characterized by limited therapeutic options and significant challenges from drug resistance development. We show that PFKFB3, an essential regulator of glycolytic metabolism, is significantly upregulated in PCa tissues and CRPC cell lines, where it plays a pivotal role in driving CRPC progression. Knockdown of PFKFB3 or inhibition by a small molecule inhibitor significantly inhibits the growth and invasion of CRPC cells, whereas overexpression promotes malignant behaviors. Mechanistically, PFKFB3 modulates the PI3K/Akt-Wnt/β-catenin pathway, resulting in enhanced tumor cell proliferation. Additionally, combining a PFKFB3 inhibitor with docetaxel produces synergistic anti-CRPC effects and reduces toxicity. Therefore, PFKFB3-mediated metabolic reprogramming underlies CRPC progression, highlighting its potential as a therapeutic target and emphasizing the need for further exploration in the development of safe and effective PFKFB3 inhibitors for precise targeted therapy in CRPC.

Ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) is an important epigenetic regulatory factor that is highly expressed in various cancers and participates in tumorigenesis and progression. However, the role and molecular mechanisms of UHRF1 in ovarian cancer (OC) remain unclear. Through survival analysis, cellular functional experiments, and animal studies, we identified UHRF1 as a key gene influencing OC progression and prognosis. Hypoxia-inducible factor-1 (HIF-1α), a well-known pro-cancer molecule, undergoes classic degradation via the ubiquitin-proteasome pathway. We discovered that UHRF1 interacts with HIF-1α, affecting its hydroxylation level, thereby inhibiting HIF-1α polyubiquitination and degradation. Functional experiments revealed that knocking down HIF-1α in stable UHRF1-overexpressing cell lines significantly reversed the malignant phenotype of OC cells. Furthermore, UHRF1 can also regulate the expression of key downstream molecules such as GLUT1, HK2, LDHA, and VEGFA by modulating HIF-1α, thus influencing tumor cell metabolism and angiogenesis. In summary, our findings suggest that UHRF1 plays a crucial role in the development of OC by regulating the expression of HIF-1α.

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.

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.

The study aimed to assess the role of CLICs in HNSCC pathogenesis and as potential disease biomarkers.

We compared the CLIC1-CLIC6 genes expression between the HNSCC tumors (n = 99) and the tissue from the free surgical margin (n = 74) at the mRNA level with RT-qPCR and at the protein level with Western Blot. To investigate the role of CLIC1-CLIC6 proteins as potential HNSCC blood biomarkers, we performed the ELISA assays on blood serum from 38 HNSCC patients and eight healthy individuals.

We found significant differences in the expression of every analyzed CLIC. At the mRNA level, CLIC1 and CLIC4 were overexpressed in oral cancer tissue, CLIC3, CLIC5, and CLIC6 were down-expressed; in laryngeal cancer tissue, CLIC2 and CLIC3 were down-expressed. Tumor staging impacted CLIC1 and CLIC6 tissue expression, and histological grade impacted CLIC6 tissue expression. At the protein level, CLIC3 was down-expressed in oral cancer tissue. Furthermore, CLIC1 and CLIC3 proteins were overexpressed, and CLIC4 and CLIC6 were down-expressed in the oral cancer patients' blood serum compared to the control group.

The different expression patterns of CLICs in HNSCC patients' tissues and blood serum suggest that they may play an essential role in HNSCC pathogenesis and serve as biomarkers for HNSCC detection.

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.

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].

To explore the specific mechanism of histone deacetylase 2 (HDAC2) mediated histone H3 lysine 27 acetylation (H3K27ac) modification in promoting the proliferation and migration of hepatocellular carcinoma cells.

Samples of 40 cases of hepatocellular carcinoma and paracancerous tissues resected from January 2021 to January 2023 were collected. The expressions of HDAC2 and H3K27ac in hepatocellular carcinoma, paracancerous tissues and cell lines were detected by immunohistochemistry and Western blotting. The correlation between the expression levels of HDAC2 and H3K27ac and the relationship between HDAC2 expression and clinicopathological characteristics of patients with hepatocellular carcinoma were analyzed. The proliferation, migration and invasion of Hep3B and HepG2 cells were determined by MTS, clone formation, scratch and Transwell experiments. The acetylation of H3K27 mediated by HDAC2 was verified by Western blotting, real-time fluorescence quantitative PCR (qRT-PCR) and chromatin immunoprecipitation high-throughput sequencing (ChIP-seq). In vivo xenotransplantation experiment, the tumorigenicity of cells in each group was measured, and the expression of proteins related to phosphoinositide 3-kinases/phosphatase and tensin homolog deleted on chromosome ten/protein kinase B/mammalian target of rapamycin (PI3K/PTEN/AKT/mTOR) signal pathway was detected.

High expression of HDAC2 and low expression of H3K27ac were found in hepatocellular carcinoma tissues and cell lines (P < 0.05), and there was a negative correlation between them (r=-0.477, P=0.002). The expression of HDAC2 was related to tumor size, hepatitis B virus infection, TNM stage and portal vein tumor thrombus (P < 0.05). Compared with the sh-NC group of Hep3B and HepG2 cells, the proliferation, clone formation, migration and invasion ability of sh-HDAC2 group were decreased (P < 0.05). Compared with the Empty group, the HDAC2 group exhibited increased expression levels and activity of HDAC2, as well as enhanced cell proliferation, clone formation, migration, invasion ability, tumor volume and mass in vivo, and elevated expression levels of p-PI3K, p-AKT, and p-mTOR (P < 0.05). Conversely, the enrichment and expression levels of H3K27ac, along with the expression level of PTEN, were decreased (P < 0.05). In the iHDAC2 group, the expression levels and activity of HDAC2, as well as the proliferation, clone formation, migration, invasion ability, tumor volume and mass in vivo, and expression levels of p-PI3K, p-AKT, and p-mTOR were reduced (P < 0.05). Additionally, the expression levels of H3K27ac and PTEN were increased (P < 0.05). To validate the involvement of the PI3K/PTEN/AKT/mTOR signaling pathway in HDAC2-mediated regulation of malignant behaviors in liver cancer cells through H3K27ac, the PI3K activator 740Y-P was introduced. Compared with the iHDAC2 group, the iHDAC2+740Y-P group exhibited increased proliferation, clone formation, migration, invasion ability, tumor volume and mass in vivo, and elevated expression levels of p-PI3K, p-AKT, and p-mTOR (P < 0.05). Conversely, the expression level of PTEN was decreased (P < 0.05).

HDAC2 initiates PI3K/PTEN/AKT/mTOR signal pathway by mediating H3K27 acetylation, which promotes the occurrence and development of hepatocellular carcinoma.

The mechanisms underlying neuropathic pain in traumatic neuromas following peripheral nerve injury have become a major research focus in the field of pain medicine. Transforming growth factor-β1 (TGF-β1), an anti-inflammatory cytokine, is significantly elevated in the dorsal root ganglion (DRG) after peripheral nerve injury. This study investigates the role and mechanisms of TGF-β1 in traumatic neuroma formation and neuropathic pain.

In vivo, neuropathic pain-related behaviors, neuroma formation, activation of nerve fibers in the dorsal root ganglion (DRG), and macrophage polarization were evaluated in rats subjected to sciatic nerve transection (SNT) to examine whether TGF-β1 plays a role in preventing traumatic neuroma. In vitro, RAW 264.7 cells were stimulated with lipopolysaccharide (LPS) (500 ng/mL) to simulate traumatic neuroma-induced pathological changes in DRG macrophages, aiming to assess whether TGF-β1 alters the balance of macrophage polarization.

In vivo, rapamycin (RAPA) treatment effectively reduced neuroma formation and alleviated neuropathic pain in rats, whereas these therapeutic effects were reversed upon inhibition of TGF-β1. In vitro, rapamycin treatment downregulated the expression of M1-related proteins (TNF-α, iNOS, and IL-1β) while upregulating M2-related proteins (Arg1 and IL-10). These effects were largely abolished when TGF-β1 siRNA was introduced. Furthermore, supplementation with exogenous recombinant TGF-β1 again reversed the M1/M2 polarization balance.

These findings suggest that TGF-β reduces the M1/M2 macrophage ratio by mediating the polarization direction of macrophages within DRGs. This mechanism may block the transmission of peripheral nociceptive signals, thereby promoting the repair of nerve injury. The study provides concrete evidence to guide the development of new therapeutic strategies for painful neuroma.

This study investigated the role of ubiquitin specific peptidase 42 (USP42) in breast cancer proliferation, focusing on its modulation of apoptosis via the JNK/p38 signaling pathway. USP42 expression levels in breast cancer cell lines were assessed using western blotting and RT-qPCR. In vitro, cell proliferation was evaluated using CCK-8 assay and clonogenic assay assessed, while apoptosis was measured by flow cytometry evaluated. Western blotting was used to analyze the expression of apoptosis-related proteins and those associated with the JNK/p38 pathway. The effect of USP42 knockdown on breast cancer cell proliferation was examined in vivo using a xenograft nude mice model. USP42 protein levels were significantly higher in breast cancer tissues than in normal breast tissues. Moreover, USP42 expression was positively correlated with the advanced T stage, N stage, and pathological stage. USP42 knockdown in MCF7 and MDA-MB-231 cells resulted in decreased proliferation and increased apoptosis rates. USP42 silencing upregulated caspase-3 and Bax expression, while downregulating Bcl-2. Phosphorylation of JNK and p38 increased significantly following USP42 silencing. Treatment with SP600125 (JNK inhibitor) or SB203580 (p38 MAPK inhibitor) effectively recused JNK and p38 activation. Both inhibitors also reduced the apoptotic cell population, which was upregulated by USP42 silencing. These findings highlight USP42 promotes breast cancer progression by reducing JNK and p38 activation and inhibiting apoptosis, suggesting its potential as a therapeutic target in breast cancer treatment.