Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and prognostically poor cancer driven by multifaceted mechanisms, notably immune evasion and drug resistance. The majority of PDAC patients present with unresectable locally advanced or metastatic disease, emphasizing a critical unmet need for effective therapies against advanced-stage pancreatic cancer. Despite the proven efficacy of the PARP inhibitor Olaparib against pancreatic cancer in patients carrying BRCA mutations, its practical use is limited by the development of acquired resistance. The clinical application of the PARP inhibitor Olaparib is limited by acquired resistance, making combination therapy a promising strategy to improve treatment responses. Exportin 1 (XPO1) is frequently overexpressed in PDAC cells, representing a therapeutic target, and its inhibitor KPT-330 has demonstrated antitumour potential. Therefore, we aim to combine Olaparib with KPT-330 to enhance its therapeutic effect against PDAC. This study aimed to investigate the synergistic antitumour effects of the combination of Olaparib and KPT-330 against PDAC and to elucidate the underlying molecular mechanisms. We applied RNA sequencing to pancreatic cancer cell lines following combination therapy to identify differentially expressed genes. Separately, Western blotting was performed to measure both the expression and phosphorylation status of key proteins within the involved signaling cascades. The combination of KPT-330 and Olaparib significantly suppressed PDAC cell viability and tumour growth. Mechanistic investigation revealed that the combination specifically reduced SGPP2 levels, leading to inhibition of the IL-6/JAK2/STAT3 signaling axis. Evidence included diminished p-JAK2 and p-STAT3, with no alteration in total JAK2 or STAT3. This SGPP2-associated synergistic effect may overcome olaparib resistance by modulating the immunosuppressive tumor microenvironment. This study reveals that the combination of Olaparib and KPT-330 enhances antitumor efficacy in pancreatic cancer by downregulating SGPP2, a tumor-associated protein, thereby inhibiting the IL-6/JAK2/STAT3 signaling pathway. SGPP2 is proposed as a key molecular node linking the two agents. Collectively, these findings provide preclinical evidence that the Olaparib and KPT-330 combination acts synergistically via the SGPP2/STAT3 axis, supporting its potential application in pancreatic cancer combination therapy.

Circular RNAs (circRNAs) are increasingly recognized as critical regulators in carcinogenesis through diverse molecular mechanisms. In this study, we reported an NSUN2-mediated methyl-5-cytosine (m5C)-dependent circSMAD2 that was significant upregulation in pancreatic cancer tissues and correlated with poor clinical outcomes. Functional analyses demonstrated that circSMAD2 overexpression promoted tumor growth in both in vitro and in vivo xenograft models. Mechanistically, cytoplasmic circSMAD2 functions as a competitive endogenous RNA by sequestering miR-769-5p, thereby relieving its repression of TRIM59 and subsequently activating the oncogenic AKT/mTOR signaling pathway. Concurrently, circSMAD2 acted as a scaffold for the interaction between IGF2BP1 and TPT1, facilitating IGF2BP1-mediated N6-methyladenosine (m6A) modification of TPT1, which further amplified AKT/mTOR pathway activation. The synergistic dual-axis activation of AKT/mTOR signaling through m5C-driven ceRNA activity and m6A-mediated posttranscriptional regulation collectively contributed to pancreatic cancer progression. Our findings establish circSMAD2 as a pivotal oncogenic driver in pancreatic cancer and highlight its potential as a diagnostic biomarker and therapeutic target for precision oncology interventions.

Background Pancreatic cancer is characterized by prolonged subclinical progression, molecular heterogeneity, and late clinical presentation, resulting in diagnosis predominantly at advanced stages. Current screening approaches lack sufficient sensitivity and scalability, underscoring the need for risk-adapted early detection strategies. Artificial intelligence (AI) offers a shift from reactive diagnosis toward proactive, precision-oriented screening. Aim of Review This review synthesizes recent advances in AI for the early screening and diagnosis of pancreatic cancer. We focus on how AI enables population-level and high-risk prediction, augments diagnostic assessment in patients with suspicious clinical, imaging, or molecular findings, and supports precision stratification through multimodal integration of radiologic imaging, circulating biomarkers, and longitudinal electronic health records (EHRs). Key Scientific Concepts of Review Advances span three domains. In imaging, deep learning models—including convolutional neural networks, transformer architectures, and self-configuring segmentation frameworks—improve pancreas segmentation, lesion detection, and classification, with several systems demonstrating radiologist-level performance in retrospective multicenter studies. In biomarker discovery, machine learning approaches such as LASSO, random forest, and XGBoost facilitate high-dimensional feature selection from transcriptomic, metabolomic, and exosomal data, enabling composite diagnostic signatures beyond CA19-9. In longitudinal EHR analysis, temporal deep learning models identify latent disease trajectories and predict pancreatic cancer risk months to years before clinical diagnosis. Despite these advances, most models remain retrospectively validated and face limitations related to data heterogeneity, interpretability, and cross-population generalizability. Conclusion AI strengthens early detection through multimodal integration, risk-adapted stratification, and data-driven clinical support aligned with precision medicine. Its near-term value lies in augmenting detection among high-risk populations rather than enabling universal screening or autonomous diagnosis. Prospective multicenter validation and improved model transparency are critical for translation into routine practice.

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and largely refractory to current therapies, underscoring the need to uncover the molecular drivers of progression to identify targetable vulnerabilities. In this study, we found that fibronectin type III domain-containing 4 (FNDC4), known for its role in macrophage polarization and metabolic regulation, was elevated in metastatic PDAC cells and correlated with poor patient outcomes. FNDC4 knockdown reduced tumor growth and metastasis in a diverse set of aggressive PDAC models. Mechanistically, FNDC4 enhanced cell cycle and apoptosis regulator 1 (CCAR1) stability, thereby sustaining CCAR1/β-catenin signaling. FNDC4 deficiency led to reduced CCAR1 and β-catenin expression and consequently impaired invasion and colony formation. Moreover, FNDC4 promoted immune evasion by driving macrophage polarization toward a protumorigenic M2 phenotype. FNDC4 loss shifted macrophage polarization toward an antitumor profile and increased CD4+ and CD8+ T-cell infiltration. Together, the effects of FNDC4 targeting resulted in reduced tumor burden, suppression of metastasis, and improved survival in immunocompetent murine PDAC models. Unexpectedly, FNDC4 localized to the nucleus, pointing to potential intranuclear activity. Transcriptomic and functional analyses further identified CCL5 as a critical downstream effector, required for recruiting CCR5+ T cells and mediating the immune effects of FNDC4 inhibition. Upstream, BHLHE40 directly activated FNDC4 transcription, which was stimulated by induction of epithelial-mesenchymal transition. Importantly, combining FNDC4 inhibition with claudin 18.2 chimeric antigen receptor T cells or chemotherapy resulted in enhanced tumor control compared with monotherapy. Together, these findings underscore the role of FNDC4 in promoting PDAC progression and the potential of FNDC4 as a target for innovative multimodal treatment strategies. SIGNIFICANCE:FNDC4 is a key driver of pancreatic cancer invasiveness and immunosuppression that can be targeted to reprogram the pancreatic tumor microenvironment and suppress tumor metastasis, offering a promising therapeutic strategy.

ABSTRACT:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and prevalent malignancy challenged by early detection, frequent presentation at advanced stages, and high likelihood of postoperative recurrence and metastasis. Despite ongoing research efforts, the 5-year survival rate for PDAC has only marginally improved. Although pharmacotherapy remains the cornerstone of multidisciplinary management strategies for PDAC, treatment options for advanced disease have historically been limited. In recent years, an increasing number of clinical trials have identified novel agents and combination therapies with promising efficacy for advanced PDAC. Immunotherapy has demonstrated significant success across various solid tumors, yet application for PDAC has so far yielded limited clinical benefit. Combination approaches integrating immune checkpoint inhibitors with chemotherapy, radiotherapy, and other therapeutic modalities have shown preliminary evidence of efficacy, although further investigation is necessary. Emerging immunotherapeutic strategies, such as adoptive cell transfer, oncolytic virotherapy, and tumor vaccines, have exhibited potential for PDAC treatment, albeit accompanied by inherent limitations. Hence, a more thorough understanding of the complex tumor microenvironment in PDAC is essential to improve the effectiveness of immunotherapeutic interventions. Personalized and precision-driven combination immunotherapies represent a promising frontier in the future of PDAC treatment. This review outlines recent advances and future perspectives in immunotherapy for PDAC, aiming to inform and enhance therapeutic strategies for this devastating malignancy.

Background Aging is a critical biological process involving multifaceted physiological and pathological changes. Recent research has revealed a complex association between aging and the development of various cancers, particularly in the pathogenesis of liver cancer and cholangiocarcinoma. Aging not only affects cell proliferation and apoptosis but also exerts a dual role in promoting or inhibiting tumorigenesis and progression by altering the cellular microenvironment and immune responses. Aim of review This review aims to critically examine the relationship between aging and the initiation and progression of liver cancer and cholangiocarcinoma, with a focus on analyzing aging-related cellular signaling pathways, changes in the microenvironment, and immune responses, among other factors. The goal is to comprehensively understand the distinct characteristics and mechanisms exhibited by these two cancers under the influence of aging.Key Scientific Concepts of Review: By synthesizing existing literature, we aim to provide new perspectives for future research and contribute to the development of early prediction and intervention strategies for liver cancer and cholangiocarcinoma.

Previous studies have demonstrated that the USP14 inhibitor IU1 and USP14/UCHL5 inhibitor b-AP15 can extend the survival period of TP53-deficient mice with spontaneous osteosarcoma (OS). However, the underlying molecular mechanisms remain to be fully elucidated. The transmembrane protein TMEM158 has been identified as a key regulator in the progression of various cancers. Nevertheless, its functional role in OS remains largely unknown. In this study, we conducted comprehensive bioinformatics analyses-including cluster analysis, differential expression analysis, and functional enrichment analysis-on clinical OS databases to assess the correlation between TMEM158 expression and the proteasome-associated USP14 and UCHL5. Primary tumor cells (TP53-deficient OS cells), SAOS-2 and U-2OS cells were treated with IU1 or b-AP15, respectively. The expression levels of TMEM158 were quantified using qPCR. Subsequently, TMEM158 was knocked down in three cell lines, and subsequent changes in cellular activity and TGF-β signaling were evaluated. Concurrently, single-cell RNA sequencing data were analyzed to identify cell types exhibiting high TMEM158 expression and to explore their associated intercellular communication patterns. Both IU1 and b-AP15 significantly prolonged the survival of TP53-deficient OS mice and exhibited enhanced cytotoxic effects on TP53-deficient OS cells. These compounds selectively suppressed TMEM158 expression in TP53-deficient primary OS and SAOS-2 cells. Bioinformatics analysis revealed that TMEM158 is positively correlated with USP14 and UCHL5 expression and serves as an independent prognostic marker for poor clinical outcomes in OS patients. Experimental validation showed that TMEM158 knockdown significantly reduced the viability of TP53-deficient primary OS and SAOS-2 cells, and inhibited TGF-β pathway activation. Osteoblastic OS cells displayed concurrent suppression of the P53 pathway and activation of the TGF-β pathway, with a strong covariant relationship between TMEM158 and activity of TGF-β pathway. Meanwhile, there may be intercellular TGF-β signaling communication between osteoblastic OS cells with high expression levels of TMEM158 and macrophages. Our findings demonstrated that the TMEM158-TGF-β pathway plays a central role in mediating the heightened sensitivity of TP53-deficient OS to USP14 inhibition. Targeting this pathway may represent a promising therapeutic strategy for precision treatment of osteosarcoma.

As a key tumor suppressor protein, p53 plays a central role in biological processes such as cell cycle regulation, DNA repair, apoptosis, and metabolism. However, p53 gene mutations or functional inactivation are prevalent in over 50% of human cancers, leading to tumorigenesis, development, and drug resistance, making it an important target for anticancer drug development. Currently, p53-targeted therapy faces challenges such as diverse mutation types, insufficient drug specificity, and drug resistance. This article systematically reviews the fundamental theories and cutting-edge advances in the development of p53-targeted drugs. It elaborates on the structure and function of p53 and its mutation-induced carcinogenic mechanisms, then focuses on analyzing the research history and clinical translation status of small-molecule drugs (e.g., APR-246), discusses the application prospects of gene therapy and immunotherapy strategies, and introduces emerging therapies based on CRISPR and PROTAC technologies. By integrating the latest research findings, this article aims to provide theoretical basis and directional guidance for the precise development and clinical translation of p53-targeted drugs.

Aberrant liquid–liquid phase separation (LLPS) can alter biomolecular condensate functions and may influence pancreatic tumorigenesis and progression, but the specific role of LLPS regulators in prognosis and the tumor immune microenvironment (TIME) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. We integrated transcriptome data of LLPS regulator–related differentially expressed genes (DEGs; n = 298) in a cohort of 176 PDAC patients from TCGA. Three LLPS regulator subtypes (LS1–LS3) were identified through multi-omics analyses, and a prognostic LLPS subtype–related risk model (LRRPC) was developed and validated. Chromatin immunoprecipitation confirmed NRF1 binding to promoters of key risk genes, and in vitro and in vivo experiments assessed the effects of NRF1 targeting on tumor growth. The three LLPS regulator subtypes exhibited significant differences in prognosis, clinical features, genomic alterations, TIME patterns and predicted immunotherapy response. The LRRPC signature predicted prognosis and immunotherapy efficacy across cohorts and was associated with tumor biomarkers and immune infiltration. Nuclear Respiratory Factor 1 (NRF1) directly regulated hub genes such as FAM83A, RHOV and ITGB6, promoting PDAC cell proliferation, while its inhibition induced apoptosis and reduced tumor growth. This study proposes an LLPS-based stratification framework for PDAC, and the LRRPC model provides an LLPS subtype–related risk score that may assist personalized prognostic assessment and immunotherapy stratification. NRF1 emerges as a promising therapeutic candidate whose targeting can inhibit tumor progression in PDAC experimental models and warrants further evaluation.

Pancreatic cancer (PC) is a highly lethal malignancy characterized by aggressive progression and limited treatment options. Current standard-of-care treatments only confer marginal survival benefits, highlighting an urgent unmet clinical need to identify novel actionable targets and mechanism-driven therapeutic regimens. Focal adhesion kinase (FAK, encoded by PTK2) is frequently dysregulated across a broad spectrum of cancers and tightly associated with malignant tumor phenotypes, yet its precise clinical relevance and druggable potential in PC remain incompletely elucidated. This study systematically evaluated the diagnostic and prognostic value of PTK2/FAK in PC, and dissected the anti-tumor efficacy and underlying molecular mechanism of the selective FAK inhibitor Defactinib. We confirmed that PTK2 was significantly overexpressed in PC tissues, serving as a high-accuracy diagnostic biomarker with an AUC of 0.959 and an independent risk factor for unfavorable prognosis. PTK2-high tumors exhibited marked enrichment of the PI3K/AKT oncogenic signaling pathway, and MYC was validated to directly transcriptionally upregulate PTK2, where patients with concurrent MYC-high and PTK2-high tumors showed the worst clinical outcomes. Using in vitro functional assays and two distinct genetically engineered mouse models, we demonstrated that Defactinib potently suppressed tumor proliferation and induced caspase-3-dependent apoptosis via blockade of the PI3K/AKT cascade. Notably, Defactinib also triggered ULK1-mediated compensatory protective autophagy, and co-administration with the autophagy inhibitor chloroquine effectively abrogated this process to substantially amplify the anti-tumor effect. Our findings validate PTK2 as a clinically meaningful prognostic biomarker and promising therapeutic target, providing robust new preclinical evidence to support the clinical translation of PTK2-targeted combination therapies for PC.

Background:High HNRNPA2B1 expression has been previously observed in diverse tumor types. On this basis, the present work focused on exploring the effects of HNRNPA2B1 on pan-cancer occurrence and progression, as well as its potential functions and molecular regulatory mechanisms. Methods:HNRNPA2B1 gene expression, protein expression, Tumor Node Metastasis (TNM) stage, and survival prognosis in thirty-three different tumors across thirty-three tumors were analyzed via The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, which included 9,664 cancer tissues and 711 normal tissues, with R software (version 3.6.3). A series of bioinformatics analyses were performed to determine the relationships between the expression of HNRNPA2B1-associated genes and prognosis, DNA promoter methylation, phosphorylation status and immune cell infiltration. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to elucidate gene functions. Cancer and corresponding para-cancerous samples were confirmed via immunohistochemistry. Results:This study confirmed that HNRNPA2B1 overexpression was associated with cancer development and a dismal prognosis in multiple types of cancer. Mutation and amplification were the main types of alterations in bladder urothelial carcinoma and esophageal adenocarcinoma, respectively. The phosphorylation and methylation levels of HNRNPA2B1 were linked to multiple tumor types. Furthermore, the HNRNPA2B1 expression level was positively correlated with infiltration degree in CESC, LIHC, HNSC-HPV+, and MESO-associated fibroblasts in TCGA. In addition, nine Chinese herbal medicines and ten Chinese medicinal plant components targeting HNRNPA2B1 were identified. Conclusions:HNRNPA2B1 affects tumor occurrence and progression. The expression of HNRNPA2B1 may serve as a reliable prognostic marker as well as a potential therapeutic target.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and often lethal malignancy, requiring the development of enhanced therapeutic approaches. The DNA damage response (DDR) pathway is frequently altered during PDAC development, leading to an increased occurrence of DNA damage. DNA topoisomerase II-binding protein 1 (TOPBP1) plays a supportive role in regulating the DDR pathway, and its overexpression has been linked to the tumorigenesis of various cancers. This study investigated the biological role of TOPBP1 in PDAC pathogenesis and evaluated its clinical relevance in guiding treatment regimens. We examined the relationship between TOPBP1 expression, DDR pathway modulation, and therapeutic response in PDAC cell lines, primary cells, and subcutaneous mouse models. We found that elevated TOPBP1 expression was positively correlated with increased histologic grade and reduced patient survival in PDAC. TOPBP1 knockdown increased the sensitivity of PDAC cells to olaparib treatment and improved therapeutic efficacy in both PDAC cell lines and subcutaneous mouse models. Combination treatment with olaparib and AZD6738 effectively induced P53-dependent apoptosis via inhibiting the ATR pathway and enhancing signaling through the ATM pathway, which significantly reduced the viability of pancreatic cell lines. Notably, this combination therapy was more effective in PDAC cell lines exhibiting high TOPBP1 expression, indicating that TOPBP1 may serve as a useful predictive biomarker. In conclusion, TOPBP1 is a potential marker for optimizing the olaparib and AZD6738 combination therapy in PDAC. This study highlights the clinical significance of TOPBP1 in the treatment of PDAC and emphasizes the potential implications for a broader population of patients.

BACKGROUND:Sialic acid-binding immunoglobulin-like lectins (SIGLECs) are widely expressed on immune cell surfaces, play an important role in maintaining immune homeostasis and regulating inflammatory responses, and are increasingly emerging as potential targets for tumor immunotherapy. However, the expression profile and crucial role of SIGLEC11 in gastric cancer (GC) remain unclear. This study aimed to elucidate the prognostic relevance of SIGLEC11 expression and its role in the immune microenvironment in patients with GC. METHODS:SIGLEC11 expression profile was analyzed using bioinformatics, immunohistochemistry, and immunofluorescence staining. Flow cytometry, mouse tumor models, patient-derived tumor organoid models, and RNA sequencing were used to explore the potential functions with the underlying mechanisms of SIGLEC11 in a coculture system of macrophages and GC cells. RESULTS:We demonstrated that SIGLEC11 was predominantly expressed in normal tissues. However, tumor-infiltrating SIGLEC11+ cells in the high SIGLEC11 expression subgroups showed poor overall survival, which was associated with the expression of an immunosuppressive regulator. Our results showed that SIGLEC11 was predominantly expressed in monocytes and macrophages and selectively upregulated in tumor-associated macrophages. Furthermore, SIGLEC11 promoted macrophage M2 polarization via AKT-mTOR signaling. In addition, SIGLEC11+ macrophages accelerate GC progression. CONCLUSIONS:The abundance of SIGLEC11+ M2-like macrophage-infiltrating tumors may serve as a biomarker for identifying immunosuppressive subtypes of GC. Thus, the potential role of SIGLEC11+ M2 macrophages as therapeutic targets warrants further investigation.

Background:Pancreatic cancer (PC) is marked by extensive heterogeneity, posing significant challenges to effective treatment. The tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), plays a critical role in driving PC progression. However, the prognostic and functional contributions of distinct CAF subtypes remain inadequately understood. Here, we introduce a novel 7-gene risk model that not only robustly stratifies PC patients but also unveils the unique role of PHLDA1 as a key mediator in tumor-stroma crosstalk. Methods:By integrating single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA sequencing data, we comprehensively characterized the heterogeneity of CAFs in PC. We identified five CAF subtypes and focused on matrix CAFs (mCAFs), which were strongly associated with poor prognosis. A 7-gene mCAF-associated risk model was constructed using advanced machine learning algorithms, and the biological significance of PHLDA1 was validated through co-culture experiments and pan-cancer analyses. Results:Our multiomics analysis revealed that the novel 7-gene model (comprising USP36, KLF5, MT2A, KDM6B, PHLDA1, REL, and DDIT4) accurately predicts patient survival, immunotherapy response, and TME status. Notably, PHLDA1 was uniquely overexpressed in CAFs and correlated with the activation of key protumorigenic pathways, including EMT, KRAS, and TGF-β, underscoring its central role in modulating the crosstalk between CAFs and malignant ductal cells. Pan-cancer analysis further supported PHLDA1's prognostic and immunomodulatory significance across multiple tumor types. Conclusion:Our study presents a novel 7-gene prognostic model that significantly enhances risk stratification in PC and identifies PHLDA1+ CAFs as promising prognostic biomarkers and therapeutic targets. These findings provide new insights into the TME of PC and open avenues for personalized treatment strategies.

Background:Despite the recent advancements in the treatment of cancer, the 5-year survival of patients with non-small cell lung cancer (NSCLC) remains unsatisfactory. Lung adenocarcinoma (LUAD) is NSCLC's most common subtype, and metastasis is the major cause of death in patients with cancer. Therefore, identifying novel targets associated with metastasis in NSCLC is crucial to improving treatment. This study aimed to characterize the expression of GNGT1 in LUAD and to clarify the mechanism underlying the association between the higher expression level of GNGT1 and worse prognosis in patients. Methods:The transcriptome datasets and clinical information of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Bioinformatics analyses were performed in 515 patients who were stratified into two groups (high- and low-GNGT1 expression group) according to the GNGT1 level. Overall survival, DNA promotor methylation, immune cell infiltration, gene set enrichment analysis (GSEA), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to elucidate the functions of GNGT1 and to identify the related hub genes in LUAD. Their expression and functions in LUAD were verified using tissues from patients and transgenic mice overexpressing GNGT1 under the control of a lung-specific promoter (Scgb1a1-Cre). Results:GNGT1 was overexpressed in patients with LUAD and was associated with poor prognosis. GNGT1 expression was significantly correlated with gene alteration and hypomethylated promoter status. High GNGT1 expression in patients with LUAD was associated with advanced lymph node metastasis and the degree of immune cell infiltration. Functional enrichment analyses indicated that differentially expressed genes (DEGs) in the high-GNGT1 group participated in DNA replication, DNA replication preinitiation, and M phase, while cell adhesion molecules, apoptosis, and natural killer cell-mediated cytotoxicity were all downregulated. Messenger RNA and protein levels were correspondingly regulated in human LUAD tissues and the Scgb1a1-Cre; LSL-GNGT1 mouse model (GNGT1fl/+ mice). Conclusions:GNGT1 was associated with tumor cell proliferation via the enhancement of tumor cell stemness and interaction with driver genes. Elevated GNGT1 expression promoted epithelial-mesenchymal transformation, remodeled the tumor microenvironment, and led to tumor metastasis, ultimately worsening the survival-related prognosis of patients with LUAD.

Diabetes mellitus (DM) represents a significant global public health challenge, as economic development and changes in modern dietary habits have contributed to a rising prevalence of DM patients. Pancreatic cancer (PC), a highly aggressive malignancy, exhibits a 5-year survival rate of approximately 10

OBJECTIVES:Gastric cancer (GC) ranks as the fourth most prevalent malignancy globally and is a leading cause of cancer-related mortality. This study aims to comprehensively investigate the pathogenesis of gastric cancer and propose innovative strategies for early diagnosis. METHODS:Leveraging data from The Cancer Genome Atlas (TCGA), we identified that hsa-miR-100-5p exhibits significantly reduced expression in gastric cancer tissues compared to normal tissues. Subsequently, the low expression levels and clinical significance of hsa-miR-100-5p were further validated through quantitative analysis in a cohort of 58 GC patients. RESULTS:Treatment with an hsa-miR-100-5p mimic markedly inhibited the proliferation of BGC823 cells, whereas the introduction of an hsa-miR-100-5p inhibitor promoted cell proliferation. A dual-luciferase reporter assay confirmed that atypical chemokine receptor 3 (ACKR3) is a direct target gene of hsa-miR-100-5p. Furthermore, our findings revealed a significant negative correlation between ACKR3 expression and hsa-miR-100-5p levels. Immunological correlation analysis suggested that ACKR3 may play a critical role in modulating the tumor microenvironment within cancer-associated fibroblasts. CONCLUSION:Collectively, these results indicate that hsa-miR-100-5p may regulate ACKR3 to enhance the migration and proliferation of GC cells, thereby contributing to the onset and progression of gastric cancer.

Background Growing evidence indicates that abnormal liquid-liquid phase separation (LLPS) can disrupt biomolecular condensates, contributing to cancer development and progression. However, the influence of LLPS on the prognosis of head and neck squamous cell carcinoma (HNSCC) patients and its effects on the tumor immune microenvironment (TIME) are not yet fully understood. Therefore, we aimed to categorize patients with HNSCC based on LLPS-related genes and explored their multidimensional heterogeneity.Methods We integrated the transcriptomic data of 3,541 LLPS-related genes to assess the LLPS patterns in 501 patients with HNSCC within The Cancer Genome Atlas cohort. Subsequently, we explored the differences among the three LLPS subtypes using multi-omics analysis. We also developed an LLPS-related prognostic risk signature (LPRS) to facilitate personalized and integrative assessments and then screened and validated potential therapeutic small molecule compounds targeting HNSCC via experimental analyses.Result By analyzing the expression profiles of 85 scaffolds, 355 regulators, and 3,101 clients of LLPS in HNSCC, we identified three distinct LLPS subtypes: LS1, LS2, and LS3. We confirmed notable differences among these subtypes in terms of prognosis, functional enrichment, genomic alterations, TIME patterns, and responses to immunotherapy. Additionally, we developed the LPRS, a prognostic signature for personalized integrative assessments, which demonstrated strong predictive capability for HNSCC prognosis across multiple cohorts. The LPRS also showed significant correlations with the clinicopathological features and TIME patterns in HNSCC patients. Furthermore, the LPRS effectively predicted responses to immune checkpoint inhibitor therapy and facilitated the screening of potential small-molecule compounds for treating HNSCC patients.Conclusion This study presents a new classification system for HNSCC patients grounded in LLPS. The LPRS developed in this research offers improved personalized prognosis and could optimize immunotherapy strategies for HNSCC.

Tumor-associated macrophages (TAMs) play a crucial physiological role in the pancreatic tumor microenvironment. However, the role of long non-coding RNAs (lncRNAs) in TAMs within pancreatic tumors remains unclear. By lncRNA sequencing between TAMs and resident macrophages from normal tissues in pancreatic cancer, it is found that H19 is highly expressed in TAMs and is correlated with the prognosis and stages of pancreatic cancer. Constructing a co-culture model of THP-1 derived TAMs and pancreatic cancer cells, H19 promotes the polarization of TAMs towards the M2 phenotype and the secretion of IL-6, IL-10, and TGF-β, both in vivo and in vitro, indirectly enhancing pancreatic cancer proliferation and metastasis. Mechanistically, H19 competitively binds to the mRNA of YTHDC1 with MiR-107, and also interacts with the YTHDC1 protein, regulating the stability of SRSF1 and thereby affecting the alternative splicing of IL-6 and IL-10. Utilizing organoids and the patient-derived xenograft (PDX) model, it is found that ruxolitinib may represent a promising treatment option for PDAC patients with high H19 expression.

RNA-binding motif protein-10 (RBM10) plays a role in pancreatic adenocarcinoma (PAAD), though its precise underlying mechanism remains unclear. The current study investigates the role of RBM10 in pancreatic cancer progression and immune regulation. RBM10 expression in pancreatic tissues from PAAD patient was assessed using Western blotting, RT-qPCR, and immunohistochemistry, revealing lower levels in pancreatic cancerous tissues compared to adjacent non-cancerous tissues. This finding aligns with in vitro experiments where RBM10 knockdown in pancreatic cancer cells enhanced colony formation, migration, and proliferation, which correlated with increased P-JAK1, P‑JAK2, and P-STAT3 levels. Bioinformatics identified RBM10-related pathways and immune changes. Moreover, RBM10 deficiency in cancer cells increased PD-1 expression in natural killer cells in vitro, reducing their tumour-killing ability. However, treatment with the JAK pathway inhibitor AZD1480 restored NK cell cytotoxicity against cancer cells. Finally, high RBM10 expression was associated with a favourable prognosis in pancreatic cancer patients, suggesting that RBM10 inhibits pancreatic cancer progression by suppressing tumour immune escape through JAK-STAT-mediated regulation of PD-1 expression in NK cells. This finding offers potential for the development of novel precision-targeted therapies in the management of pancreatic cancer.