Dysbiosis–NK Cell Crosstalk in Pancreatic Cancer: Toward a Unified Biomarker Signature for Improved Clinical Outcomes

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 730 - 730

Published: Jan. 16, 2025

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME), which contributes treatment resistance. Recent research shows that the microbiome, including microbial communities in oral cavity, gut, bile duct, and intratumoral environments, plays a key role PDAC development, imbalances (dysbiosis) promoting inflammation, progression, therapy resistance, side effects. Microbial metabolites can also affect immune cells, especially natural killer (NK) are vital for surveillance, response treatment-related Dysbiosis NK cell function, leading resistance We propose combined biomarker approach, integrating microbiome composition profiles, help predict effects, enabling more personalized therapies. This review examines how dysbiosis dysfunction discusses strategies (e.g., antibiotics, probiotics, vaccines) modulate enhance function. Targeting could activity, improve effectiveness of treatments, reduce However, further needed develop unified cell–microbiome interaction-based biomarkers precise effective patient outcomes.

Language: Английский

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A high-fat diet induces changes in mesenteric adipose tissue accelerating early-stage pancreatic carcinogenesis in mice

The Journal of Nutritional Biochemistry, Journal Year: 2024, Volume and Issue: 131, P. 109690 - 109690

Published: June 13, 2024

Increased adiposity is a significant risk factor for pancreatic cancer development. Multiple preclinical studies have documented that high-fat, high calorie diets, rich in omega-6 fatty acids (FA) accelerate However, the effect of low sucrose diet (HFD), on carcinogenesis remains unclear. We evaluated impact HFD early-stage clinically relevant Kras

Language: Английский

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The Oncoprotein Mucin 1 in Pancreatic Cancer Onset and Progression: Potential Clinical Implications

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 275 - 275

Published: Feb. 13, 2025

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by poor prognosis, therapeutic resistance, and frequent recurrence. Current options for PDAC include surgery, radiotherapy, immunological targeted approaches. However, all these therapies provide only slight improvement in patient survival. Consequently, the discovery of novel specific targets becoming priority to develop more effective treatments PDAC. Mucin 1 (MUC1), transmembrane glycoprotein, aberrantly glycosylated frequently overexpressed pancreatic cancer. Recent studies highlighted role this oncoprotein carcinogenesis its involvement acquisition typical aggressive features PDAC, like local invasion, metastases, drug resistance. This review explores mechanisms which MUC1 contributes cancer onset progression, with focus on potential as biomarker target treatment.

Language: Английский

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STAT3 Signaling Pathway in Health and Disease

MedComm, Journal Year: 2025, Volume and Issue: 6(4)

Published: March 30, 2025

ABSTRACT Signal transducer and activator of transcription 3 (STAT3) is a critical factor involved in multiple physiological pathological processes. While STAT3 plays an essential role homeostasis, its persistent activation has been implicated the pathogenesis various diseases, particularly cancer, bone‐related autoimmune disorders, inflammatory cardiovascular neurodegenerative conditions. The interleukin‐6/Janus kinase (JAK)/STAT3 signaling axis central to activation, influencing tumor microenvironment remodeling, angiogenesis, immune evasion, therapy resistance. Despite extensive research, precise mechanisms underlying dysregulated disease progression remain incompletely understood, no United States Food Drug Administration (USFDA)‐approved direct inhibitors currently exist. This review provides comprehensive evaluation STAT3's health disease, emphasizing involvement cancer stem cell maintenance, metastasis, inflammation, drug We systematically discuss therapeutic strategies, including JAK (tofacitinib, ruxolitinib), Src Homology 2 domain (S3I‐201, STATTIC), antisense oligonucleotides (AZD9150), nanomedicine‐based delivery systems, which enhance specificity bioavailability while reducing toxicity. By integrating molecular mechanisms, pathology, emerging interventions, this fills knowledge gap STAT3‐targeted therapy. Our insights into crosstalk, epigenetic regulation, resistance offer foundation for developing next‐generation with greater clinical efficacy translational potential.

Language: Английский

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Suppressing Pancreatic Cancer Survival and Immune Escape via Nanoparticle-Modulated STING/STAT3 Axis Regulation

Bioconjugate Chemistry, Journal Year: 2024, Volume and Issue: 35(11), P. 1815 - 1822

Published: Oct. 18, 2024

Pancreatic ductal adenocarcinoma (PDAC) poses a challenge in oncology due to its high lethality and resistance immunotherapy. Recently, emerging research on the stimulator of interferon gene (STING) pathway offers novel opportunities for Although STING expression is retained PDAC cells, response cells agonists remains ineffective. Signal transducer activator transcription 3 (STAT3), downstream STING, notably overexpressed pancreatic cancer related tumor survival immune escape. We observed that inhibiting STAT3 signaling post-STING activation effectively suppressed growth through signal 1 (STAT1)-mediated apoptosis but led potential risk immune-related adverse events (irAEs). To address this issue, we designed tumor-penetrating liposome codelivery agonist inhibitor. These nanoparticles regulated STING/STAT3 axis inhibited proliferation tumor. Simultaneously, found significant increase NK CD8

Language: Английский

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The long non-coding RNA NEAT1 contributes to aberrant STAT3 signaling in pancreatic cancer and is regulated by a metalloprotease-disintegrin ADAM8/miR-181a-5p axis

Cellular Oncology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 16, 2024

Abstract Purpose Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and several studies demonstrate that STAT3 has critical roles throughout course PDAC pathogenesis. Methods TCGA, microarray, immunohistochemistry data from a cohort were used for clinical analyses. Panc89 cells with ADAM8 knockout, re-expression mutants, Panc1 overexpressing generated. Gene expression analyses ADAM8, STAT3, long non-coding (lnc) RNA NEAT1, miR-181a-5p ICAM1 performed by quantitative PCR. Subcellular fractionation quantified NEAT1 in cytoplasm nucleus cell lines. Cell proliferation, scratch, invasion assays to detect growth rate, migration capabilities cells. Gain loss function experiments carried out investigate biological effects lncRNA on downstream genes. Dual-luciferase reporter gene assay determined interaction binding sites NEAT1. Pull down assays, protein immunoprecipitation (RIP), ubiquitination explored molecular between STAT3. Results High causes aberrant signaling positively correlated expression. was confirmed prevents degradation proteasome as increased observed knockout treated bortezomib. Furthermore, miRNA-181a-5p regulates direct promoter. Conclusion intracellular levels via pancreatic cancer.

Language: Английский

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Aberrant STAT3 signaling in pancreatic cancer requires the lncRNA NEAT1 regulated by the metalloprotease-disintegrin ADAM8 via miR-181a-5p

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: July 3, 2024

Purpose Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Several studies demonstrate that ADAM8 and STAT3 are critical for PDAC progression potential therapeutic targets. Methods TGCA, microarray, immunohistochemistry data from a cohort were used clinical analyses. Panc89 cells with knockout, re-expression mutants, Panc1 overexpressing generated. Gene expression analyses ADAM8, STAT3, long non-coding (lnc) RNA NEAT1, miR-181a-5p ICAM1 performed by quantitative PCR. Subcellular fractionation quantified NEAT1 in cytoplasm nucleus cell lines. Cell proliferation, scratch, invasion assays to detect growth rate, migration capabilities cells. Gain loss function experiments carried out investigate biological effects lncRNA on downstream genes. Dualluciferase reporter gene assay determined interaction binding sites NEAT1. Pull down assays, protein immunoprecipitation (RIP), ubiquitination explored molecular between STAT3. Results High causes aberrant signaling activation genes positively correlated expression. was confirmed prevents degradation proteasome as increased observed knockout treated bortezomib. Furthermore, miRNA-181a-5p whose controlled regulates direct promoter. Conclusion intracellular levels via pancreatic cancer.

Language: Английский

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Enhancing Chemoimmunotherapy for Colorectal Cancer with Paclitaxel and Alantolactone via CD44-Targeted Nanoparticles: A STAT3 Signaling Pathway Modulation Approach

Asian Journal of Pharmaceutical Sciences, Journal Year: 2024, Volume and Issue: 20(1), P. 100993 - 100993

Published: Nov. 12, 2024

Chemoimmunotherapy has the potential to enhance chemotherapy and modulate immunosuppressive tumor microenvironment by activating immunogenic cell death (ICD), making it a promising strategy for clinical application. Alantolactone (A) was found augment anticancer efficacy of paclitaxel (P) at molar ratio 1:0.5 (P:A) through induction more potent ICD via modulation STAT3 signaling pathways. Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents, thereby enhancing multi-drug chemoimmunotherapy. To improve targeting ability bioavailability hydrophobic drugs, an amphiphilic prodrug conjugate (HA-PTX) chemically modified (PTX) hyaluronic acid (HA) as backbone. Based on this concept, CD44-targeted nanodrugs (A@HAP NPs) were developed co-delivery A P in colorectal cancer treatment, aiming achieve synergistic toxicity-based chemo-immunotherapy. The uniform size high loading capacity A@HAP NPs facilitated their accumulation within tumors enhanced permeability retention effect well HA-mediated targeting, providing solid foundation subsequent therapy immunoregulation. In vitro vivo studies demonstrated that exhibited cytotoxicity against cells while also remodeling immune-suppressive promoting antigen presentation inducing dendritic maturation, thus offering novel approach

Language: Английский

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