Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies and characterized by pronounced heterogeneity and widespread dysregulation of microRNAs (miRNAs) that influence epithelial-to-mesenchymal transition (EMT) and metastasis. Tumor-derived extracellular vesicles (tEVs) further contribute to TNBC progression by transporting oncogenic cargo that can enhance pro-inflammatory signaling. The synthetic SMRwt peptide has been suggested to modulate oncogenic pathways; however, its effects on EV miRNA composition and inflammatory transcript profiles in TNBC remain unclear. Here, we investigated whether SMRwt alters tEV-associated miRNAs and cytokine transcript signatures relevant to EMT and inflammasome-linked pathways. Extracellular vesicles were isolated from SMR-treated and untreated MDA-MB-231 cells, followed by nanoparticle tracking analysis and small RNA sequencing. SMRwt treatment enriched 11 tumor-suppressive miRNAs (including Let-7a-5p, Let-7b-5p, miR-24-3p, miR-26b-5p, miR-92a-3p, miR-93-5p, and miR-496) previously associated with the regulation of proliferation, EMT, migration, and metastasis. We also observed modest, non-significant decreases (1.01-1.27-fold) in oncogenic miR-1200, miR-374a-5p, and miR-937-3p, which have been implicated in the progression of breast, lung, and bone malignancies. Complementary transcriptomic profiling using the NanoString nCounter Breast Cancer 360 Gene Expression Panel (NanoString Technologies, Inc., Seattle, CA, USA) demonstrated reduced expression of inflammasome-associated cytokines in TNBC cells relative to non-tumorigenic controls, including a log₂ fold change of -1.15 for IL 1β (MDA-MB-231 vs. MCF10A). These transcript-level changes suggest potential modulation. Additionally, SMRwt suppresses ASC-mediated caspase-1 activation and reduces IL-1β secretion, thereby inhibiting NLRP3 inflammasome signaling. Therefore, we infer that SMRwt simultaneously restores tumor-suppressive miRNA networks and suppresses inflammasome-driven inflammation, supporting its potential as a dual-target therapeutic strategy for TNBC.

Inflammation is widely viewed as a driver of hepatocellular carcinoma (HCC), yet inflammatory signaling also reshapes hepatic xenobiotic metabolism. Here, we established transgenic (Tg) IKKβ^Δhep mice (Tg-IKKβ^Δhep), which combine hepatocyte-specific IKKβ deletion with liver expression of a nuclear, kinase-inactive IKKβ mutant (NLS-IKKβKN). Tg-IKKβ^Δhep mice developed spontaneous chronic hepatitis and progressive fibrosis but were strikingly resistant to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, with markedly reduced tumor multiplicity and total tumor burden. Despite persistent inflammatory injury, DEN-triggered oxidative DNA damage and p53 activation were markedly attenuated, compatible with reduced tumor initiation. Transcriptomic and biochemical analyses revealed broad repression of xenobiotic-metabolizing cytochrome P450 genes, including the pericentral enzyme CYP2E1, accompanied by reduced CYP2E1 protein abundance. This was associated with impaired HNF4α-PXR-CAR transcriptional output and reduced HNF4α occupancy at target promoters. Acute TNFα or IL-1β exposure recapitulated this repression, in part through reduced PGC-1α expression and decreased RNA polymerase II recruitment to target promoters. In parallel, pericentral xenobiotic metabolism was blunted, a change that could plausibly diminish DEN bioactivation and genotoxic stress. Together, these findings support a "metabolic gatekeeping" model in which chronic inflammation can constrain chemical hepatocarcinogenesis by attenuating carcinogen-metabolizing capacity.

Glioblastoma (GBM) is a highly aggressive brain tumor with a complex tumor microenvironment (TME) that includes immune cell infiltration, notably macrophages. The role of macrophages in GBM progression is influenced by their polarization state, which can be either pro-inflammatory (M1) or immunosuppressive (M2). This study investigates the macrophage polarization in GBM, identifying key macrophage-related genes and their impact on tumor progression. Analysis of TCGA-GBM data revealed that macrophage infiltration correlates with poor prognosis, with 41 risk-associated genes identified. DSP dataset analysis highlighted 378 differentially expressed genes between CD68⁺ macrophages and GFAP⁺ controls, including immune-related genes like SPP1, CD74, and C3. Cross-validation with single-cell RNA-seq confirmed the expression of 9 key genes, with 7 genes being macrophage-specific. In vitro experiments using conditioned media from GBM cell lines demonstrated that GBM cells promote macrophage polarization towards an M2-like phenotype. Overexpression of CD74, CLEC7A, and IFI30 in macrophages further enhanced M2 polarization, which was associated with increased tumor-promoting functions, including enhanced invasion and reduced apoptosis in GBM cells. Together, these findings highlight the role of M2 macrophage polarization in promoting GBM progression and suggest that targeting macrophage polarization pathways may offer therapeutic potential.

Endometrial cancer (EC) is the leading gynecological malignancy worldwide. Obesity is reported to be associated with 50% of EC cases. Significant gaps remain in investigating specific molecular mechanisms behind the obesity-driven EC. Women diagnosed with EC undergoing total hysterectomy were recruited. Patients were divided into two groups: EC-obese with BMI > 29.9 kg/m² (n = 10) and EC-Non-obese with BMI ≤ 29.9 kg/m² (n = 10). Tumor tissues were subjected to label-free quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differentially expressed proteins were identified and subjected to pathway enrichment and network analyses to characterize obesity-associated alterations. Proteomic profiling showed a significant dysregulation of 456 proteins: 171 upregulated and 285 downregulated. Proteins involved in endoplasmic reticulum quality control particularly endoplasmic reticulum lectin 1 (ERLEC1), were reduced. Conversely, EC-obese demonstrated upregulation of hepatocyte growth factor (HGF), integrin-linked kinase (ILK), CTTNBP2 N-terminal-like protein (CTTNBP2NL), and lysyl oxidase homolog 1 (LOXL1), implicating activation of inflammatory pathways. Bioinformatic analysis showed downregulation of immune-related pathways, including neutrophil degranulation, complement activation in the EC-obese group. ROC analysis identified apolipoprotein(a), phospholipase B-like 1, CTTNBP2NL, and ILK as significant proteins that can differentiate between the obese and non-obese states. Our findings provide insights into obesity-associated proteomic changes in EC and highlight candidate proteins that can be used for molecular stratification after further validation.

Radiotherapy remains an irreplaceable treatment modality for breast cancer (BC). Calmodulin‑binding Transcription Activator 1 (CAMTA1) has been implicated in tumor progression; however, its role in BC is unclear. The present study aimed to elucidate the mechanistic function of CAMTA1 in BC. RNA sequencing was performed on RAW264.7 macrophages co‑cultured with 4T1 cells and subjected to X‑ray irradiation. In vitro, THP‑1 cells were co‑cultured with MDA‑MB‑231 cells under hypoxic conditions. Exosome morphology was observed under transmission electron microscopy and PKH67 staining was used to trace exosome uptake. Flow cytometry was used to detect CD163 expression while ELISA measured the levels of IL‑10 and IL‑12. Reverse transcription‑quantitative (RT‑q) PCR and immunoblotting analysis were used to detect the expressions of neuregulin 1 (NRG1), CAMTA1 and hypoxia‑inducible factor‑1α. Cell apoptosis, cell cycle distribution, cell viability and proliferation were evaluated using flow cytometry, MTT assay and colony formation assay. In vivo, transfected MDA‑MB‑231 cells were injected into BALB/c nude mice combined with radiotherapy and exosome injection. Histopathological changes in tumor tissues were examined using H&E staining. Immunohistochemistry analysis was performed to assess the expressions of NRG1, Caspase‑3 and CD163. RNA sequencing, RT‑qPCR and immunoblotting analysis revealed that NRG1 expression was markedly increased in RAW264.7 macrophages co‑cultured with 4T1 cells. NRG1 was found to be involved in M2 polarization induced by hypoxia‑treated MDA‑MB‑231 cells, which in turn promoted radio‑resistance. CAMTA1 expression was highly expressed in exosomes derived from hypoxic MDA‑MB‑231 cells and exosomal CAMTA1 promoted the M2 polarization of THP‑1 macrophages. In vivo, CAMTA1 overexpression greatly enhanced tumor growth, increased NRG1 expression, inhibited cell apoptosis and promoted M2 polarization of macrophages in tumor tissue. MDA‑MB‑231 cells were found to deliver CAMTA1 to macrophages via exosomes, leading to upregulation of NRG1 and induction of M2 polarization, thereby enhancing BC cells resistance to radiotherapy. These findings provided novel insights into the mechanisms underlying radio‑resistance in BC and identify exosomal CAMTA1 as a potential therapeutic target.

Ovarian cancer (OV) remains the most lethal gynecological malignancy, owing to late‑stage diagnosis, high metastatic potential and limited therapeutic efficacy. Although the transcription factor zinc finger and BTB domain‑containing 7A (ZBTB7A) has been implicated in several types of cancer, its role in OV has not yet been systematically characterized. The present study comprehensively investigated the expression pattern, prognostic relevance, functional role and downstream mechanisms of ZBTB7A in OV progression. Multi‑cohort transcriptomic analyses across independent public datasets revealed consistent upregulation of ZBTB7A in OV tissues, and high expression predicted a significantly poor prognosis. Single‑cell RNA sequencing demonstrated that ZBTB7A‑high tumor cells were enriched in proliferative, migratory and epithelial‑mesenchymal transition‑related programs, accompanied by activation of oncogenic pathways such as Wnt/β‑catenin and Hippo‑YAP. Functional assays using overexpression and RNA interference demonstrated that ZBTB7A enhanced malignant phenotypes, including increased cell proliferation, DNA synthesis, clonogenic survival and migration. Further analyses identified cytokine receptor‑like factor 1 (CRLF1) as a key downstream effector of ZBTB7A. ZBTB7A overexpression elevated CRLF1 transcription, whereas CRLF1 knockdown abrogated ZBTB7A‑induced proliferation and migration, defining a functional ZBTB7A/CRLF1 oncogenic axis. Collectively, these findings establish ZBTB7A as an important transcriptional driver of OV aggressiveness and highlight the ZBTB7A/CRLF1 regulatory pathway as a potential prognostic biomarker and therapeutic target.

Src phosphorylation (activation) is associated with the proliferation and survival of numerous human cancer cells. The role of Src phosphorylation and expression, as well as its pharmacological inhibition by PP1, a Src inhibitor, in the growth of oral squamous cell carcinoma (OSCC), remain unclear. The present study explored whether Src is expressed and phosphorylated in HSC‑3 human oral cancer cells and whether PP1 treatment affects the proliferation of these cells. Src was found to be highly expressed and phosphorylated in HSC‑3 human oral cancer cells. Notably, treatment with PP1 at 10 µM significantly reduced cell proliferation and induced apoptosis, evidenced by DNA fragmentation, caspase‑9 and ‑8 activation, and poly(ADP‑ribose) polymerase cleavage. Mechanistically, PP1 not only inhibited Src phosphorylation but also disrupted a broad network of oncogenic pathways, including EGFR, JAK2, STAT‑3, PKB and ERK‑1/2 in HSC‑3 cells. Furthermore, PP1 induced markers of ER stress and inhibited protein translation, as shown by increased eIF‑2α phosphorylation and decreased S6 phosphorylation. The critical role of Src was confirmed by pharmacological inhibition and further validated when small interfering RNA‑mediated knockdown mimicked the anti‑proliferative effects of PP1. Importantly, these potent anticancer effects were conserved in another OSCC cell line (YD‑10B) and, were validated in vivo, where PP1 suppressed tumor growth in a zebrafish xenograft model. Collectively, these findings suggest that PP1 exerts strong anticancer effects on human oral cancer by simultaneously inhibiting Src activity and disrupting a network of associated oncogenic pathways (EGFR, STAT‑3, PKB and ERK‑1/2).

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, regarding the cell migration assay data shown in Fig. 4A on p. 432, the 'EC109' and 'Vector' data panels were found to contain an overlapping section, such that data which were intended to show the results of differently performed experiments were apparently derived from the same original source. The authors have been contacted by the Editorial Office to offer an explanation for the apparent anomaly in the presentation of the data in their paper, and we are awaiting their response. 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 Molecular Medicine 27: 429-434, 2011; DOI: 10.3892/ijmm.2011.603].

HCC is a prevalent malignant tumor globally with high mortality. MiR-500a-3p plays critical roles in tumorigenesis and tumor progression.

To evaluate miR-500a-3p's role in HCC, we first analyzed its expression and prognostic value via qRT-PCR and TCGA (Kaplan-Meier analysis). We then performed extensive in vitro functional studies after cell transfection (mimics, anti-miR, SOCS2 OE), measuring proliferation, migration, invasion, glycolytic parameters (glucose consumption, lactate, ECAR, ATP), and apoptosis. A target relationship with SOCS2 was predicted bioinformatically and confirmed by dual-luciferase assay. Using the JAK2/STAT5 signaling pathway inhibitor Fedratinib, the activator Erythropoietin, and transfection with si-STAT5 and oe-STAT5, the molecular mechanism of miR-500a-3p in HCC was investigated. In vivo experiments established tumor-bearing mouse models to evaluate the effect of miR-500a-3p on tumor growth.

miR-500a-3p was significantly upregulated in HCC tissues and cells, and was associated with poor patient prognosis. The overexpression of miR-500a-3p promotes the malignant progression of HCC cells. Mechanistically, miR-500a-3p directly targeted and negatively regulated SOCS2 expression. SOCS2 expression was suppressed in HCC, with its expression abrogating miR-500a-3p-mediated oncogenicity. miR-500a-3p activated the JAK2/STAT5 pathway by inhibiting SOCS2, thereby regulating the malignant biological behaviors of HCC cells. Both SOCS2 overexpression and JAK2 inhibitor treatment could reverse the activation of the JAK2/STAT5 axis and downstream effects induced by miR-500a-3p. MiR-500a-3p promoted tumor growth in tumor-bearing mice, accompanied by SOCS2 downregulation and JAK2/STAT5 pathway activation.

This study reveals that miR-500a-3p promotes proliferation and glycolysis while inhibiting apoptosis of HCC cells by negatively regulating SOCS2 and activating the JAK2/STAT5 pathway.

Tumor-associated macrophages (TAMs) represent the most abundant immune cell population within the tumor microenvironment and play a critical role in cancer progression. However, the molecular mediators underlying TAM-driven tumor invasion remain incompletely defined. This study investigated whether ADAM9 functions as a key effector of pro-invasive TAM polarization using a canine mammary tumor model integrated with human transcriptomic datasets.

Transcriptomic analyses were performed using canine and publicly available human datasets. Single-cell RNA sequencing was used to determine cellular localization of ADAM9. IL-4-induced M2 macrophages were evaluated for ADAM9 expression, tumor migration and invasion capacity, extracellular matrix (ECM) degradation, cytoskeletal remodeling, and spheroid destabilization. ADAM9 knockdown and cancer stem cell (CSC)-conditioned medium experiments were conducted to assess mechanistic involvement.

ADAM9 was consistently enriched in M2-polarized TAMs across species and was confirmed to be expressed in TAM populations by single-cell RNA sequencing. IL-4-induced M2 macrophages upregulated ADAM9 and significantly enhanced tumor migration and invasion. ADAM9 knockdown attenuated ECM degradation, reduced MMP9 expression, and disrupted F-actin remodeling. CSC-conditioned medium further induced ADAM9 expression, suggesting its role as a convergent mediator of CSC-macrophage crosstalk. In spheroid models, ADAM9 depletion prevented TAM-mediated spheroid destabilization and suppressed collective invasion.

These findings identify ADAM9 as a key effector of TAM-driven tumor invasion through ECM remodeling and cytoskeletal regulation, and highlight ADAM9 as a promising therapeutic target within the tumor immune microenvironment.