Translational Oncology最新文献

{"title":"Metformin as a promising therapeutic agent for papillary thyroid cancer: Mechanisms of antitumor and pro-apoptotic activity","authors":"Katarzyna Wincenciuk ,&nbsp;Angelika Buczyńska ,&nbsp;Adam Jacek Krętowski ,&nbsp;Agnieszka Adamska","doi":"10.1016/j.tranon.2025.102483","DOIUrl":"10.1016/j.tranon.2025.102483","url":null,"abstract":"<div><div>Metformin, a well-established modulator of various metabolic pathways, including those regulating glucose and lipid metabolism, hormone synthesis, oxidative stress, and apoptosis, has garnered increasing interest in the field of cancer treatment and prevention. Clinical studies have indicated a reduced incidence of cancer in patients with type 2 diabetes mellitus who were treated with metformin. Emerging research has illuminated the underlying antitumor mechanisms of metformin, primarily through its activation of AMP-activated protein kinase (AMPK) and the concomitant inhibition of the mammalian target of rapamycin (mTOR) pathway. These molecular events culminate in the induction of apoptosis. Notably, investigations involving human papillary thyroid cancer (PTC) cells have demonstrated metformin's antimitogenic activity, which is closely linked to its ability to inhibit cellular proliferation and metastasis. Given the rising incidence of PTC in recent decades, there is an urgent need to explore innovative and minimally invasive treatment strategies. Consequently, the exploration of metformin as an adjunctive therapy for PTC has become a topic of critical importance, as it has the potential to effectively impede tumor cell proliferation and promote apoptosis. However, it is important to recognize the current limitations in the evidence supporting the anticancer properties of metformin. Most findings stem from <em>in vitro</em> studies, which may not fully capture the complexities of human physiology. Therefore, the primary objective of this literature review is to comprehensively synthesize recent advancements regarding metformin's anticancer and proapoptotic effects, with particular emphasis on its role in ongoing clinical trials targeting PTC intervention.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102483"},"PeriodicalIF":5.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timosaponin AIII inhibits gastric cancer by causing oxidative stress and blocking autophagic flux","authors":"Chunyang Zhu ,&nbsp;Shuming Chen ,&nbsp;Yangyang Lu,&nbsp;Jialin Song,&nbsp;Shasha Wang,&nbsp;Jing Guo,&nbsp;Xiaoxi Han,&nbsp;YuanYuan Fang,&nbsp;Siyi Zhang,&nbsp;Wensheng Qiu,&nbsp;Weiwei Qi","doi":"10.1016/j.tranon.2025.102481","DOIUrl":"10.1016/j.tranon.2025.102481","url":null,"abstract":"<div><h3>Background</h3><div><strong>:</strong> Gastric cancer (GC) is a prevalent malignant tumor worldwide, with limited treatment targets. Timosaponin AIII (Tim AIII) is the naturally steroid saponin isolated from Anemarrhena, while this study initially confirms the anti-GC effect of Tim AIII.</div></div><div><h3>Methods</h3><div><strong>:</strong> MTT assay, cell cycle analysis, and wound healing assay were used to evaluate the inhibitory effects of Tim AIII on GC cells (AGS and HGC27). Evaluate the oxidative stress (OS) by measuring reactive oxygen species (ROS) and malondialdehyde (MDA), as well as the Kelch-like ECH-associated protein 1 (Keap1) - Nuclear factor erythroid-derived 2-like 2 (Nrf2) pathway. RNA sequencing and proteomics analysis were utilized to investigate deeper molecular mechanisms. To track the autophagic flux using transmission electron microscope, detecting changes in autophagy-related pathway proteins, staining with LC3B and lysosome. Experiments related to cell viability, OS, and autophagy levels were performed on normal gastric mucosal epithelial cells (GES-1) as parallel controls. Finally, Nude mouse subcutaneous tumor model to evaluate the anti-GC ability in vivo.</div></div><div><h3>Results</h3><div><strong>:</strong> Tim AIII inhibits the viability, proliferation, and migration of GC cells. Tim AIII causes OS in GC cells by the increasing intracellular ROS and MDA levels and inhibiting the Keap1-Nrf2 pathway. RNA sequencing and proteomics analysis mainly focused on the autophagy-associated pathways and lysosome in GC cells. Tim AIII activates autophagy, as indicated by an increase in the number of autophagosomes, inhibition of the PI3K-AKT pathway, and activation of the AMPK pathway in GC cells. However, Tim AIII inhibits autophagy-lysosome fusion and impairs lysosomal function, which results in autophagic flux blockage in GC cells. The Tim AIII concentration that significantly inhibited GC cells in this study was applied to GES-1 cells. The results showed that at this concentration, Tim AIII exhibited no significant cytotoxic effects on GES-1 cells, did not induce OS, and had no impact on autophagy. Finally, Tim AIII also has the ability to inhibit tumor growth in vivo.</div></div><div><h3>Significance</h3><div><strong>:</strong> In summary, the results of our study indicate Tim AIII as a novel late-stage autophagy inhibitor, which may provide novel medical possibilities for GC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102481"},"PeriodicalIF":5.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognosticating salvage stereotactic radiosurgery outcomes in relapsed primary central nervous system lymphoma: A machine learning-driven decision tree analysis","authors":"Huili Zhao ,&nbsp;Shenao Zhang ,&nbsp;Lang Chen ,&nbsp;Xin Liu ,&nbsp;Aihong Cao ,&nbsp;Peng Du","doi":"10.1016/j.tranon.2025.102482","DOIUrl":"10.1016/j.tranon.2025.102482","url":null,"abstract":"<div><h3>Purpose</h3><div>To identify key clinical risk factors affecting therapeutic outcomes in relapsed primary central nervous system lymphoma (r-PCNSL) patients undergoing stereotactic radiosurgery salvage therapy (SRS-ST) and develop a decision tree-based predictive model.</div></div><div><h3>Patients and Methods</h3><div>A retrospective analysis was performed on r-PCNSL patients undergoing SRS-ST at The Second Affiliated Hospital of Xuzhou Medical University between January 2012 and November 2021. The cohort was randomly divided into training and validation sets (7:3 ratio). The C5.0 algorithm was employed to develop a decision tree model for predicting treatment response. Model performance was evaluated using diagnostic metrics including accuracy (ACC), sensitivity, and specificity.</div></div><div><h3>Results</h3><div>A cohort of 209 patients meeting inclusion/exclusion criteria were enrolled. Survival analysis revealed a mean progression-free survival (PFS) of 7.5 ± 2.6 months and overall survival (OS) of 13.8 ± 4.1 months. Using multivariate analysis, a decision tree model was developed incorporating three critical prognostic parameters: Karnofsky Performance Status (KPS); deep brain structure involvement; and International Extranodal Lymphoma Study Group (IELSG) score. The model demonstrated robust predictive accuracy, with sensitivities of 0.880-1.000 in the training set versus 0.667-0.880 in the validation set, and corresponding specificities of 0.926-1.000 and 0.854-0.984, respectively.</div></div><div><h3>Conclusions</h3><div>Our analysis identified critical determinants of therapeutic response in r-PCNSL patients receiving SRS-ST, developing a clinically applicable decision tree model to guide hematologists and neuro-oncologists in personalizing treatment approaches.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102482"},"PeriodicalIF":5.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline mutation analysis and postoperative recurrence risk prediction in breast cancer patients from western China","authors":"Zhujun Deng ,&nbsp;Xia Xiao ,&nbsp;Biqin Mou,&nbsp;Jing Wang,&nbsp;Qiongxia Hu,&nbsp;Juan Jiang,&nbsp;Kang Xie,&nbsp;Wengeng Zhang,&nbsp;Weimin Li,&nbsp;Bojiang Chen","doi":"10.1016/j.tranon.2025.102477","DOIUrl":"10.1016/j.tranon.2025.102477","url":null,"abstract":"<div><h3>Background</h3><div>Much of our understanding of the germline mutation spectrum derives from hereditary breast cancer data in white populations. Additionally, the influence of genetic variants on breast cancer prognosis remains a topic of debate. Identifying patients at high risk of postoperative recurrence is crucial for guiding clinical decision-making; however, there is currently no reliable multigene risk prediction model tailored to the Chinese population.</div></div><div><h3>Methods</h3><div>A single-center retrospective study involving 1067 breast cancer patients was conducted. Survival analyses were performed using the Kaplan‒Meier method and Cox proportional hazards regression. Postoperative recurrence risk prediction models were developed utilizing the Cox regression methodology.</div></div><div><h3>Results</h3><div>In this cohort, 229 germline pathogenic/likely pathogenic (P/LP) mutations were identified in 215 patients (20.1 %). No significant differences in disease-free survival (DFS) were observed between germline P/LP mutation carriers and non-carriers. However, 10 single-nucleotide polymorphisms (SNPs) were significantly associated with DFS outcomes. By integrating the SNP status and clinical phenotype, a postoperative recurrence risk prediction model was established. The area under the curve values for 1- and 3-year DFS in the training set were 0.840 and 0.754. This model can accurately predict the DFS of patients in both the training set (hazard ratio [HR] 5.23, 95 % confidence interval [CI] 2.96–9.34; <em>p</em> &lt; 0.0001) and the validation set (HR 2.88, 95 % CI 1.41–6.06; <em>p</em> = 0.003)</div></div><div><h3>Conclusion</h3><div>In patients with early and locally advanced breast cancer, SNPs, rather than germline P/LP mutations, impact DFS. Using a genetic-clinical model, we successfully identified patients at high risk of postoperative recurrence.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102477"},"PeriodicalIF":5.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aptamer-mediated delivery of therapeutic oligonucleotides in glioblastoma","authors":"Giorgia Castellani ,&nbsp;Mariachiara Buccarelli ,&nbsp;Enza Cece ,&nbsp;Martina Offi ,&nbsp;Lucia Ricci-Vitiani","doi":"10.1016/j.tranon.2025.102485","DOIUrl":"10.1016/j.tranon.2025.102485","url":null,"abstract":"<div><div>Aptamers are single-stranded oligonucleotides with great versatility, acting as therapeutic molecules with anticancer properties but also as delivery systems. A growing number of studies showed that aptamers can be properly designed to recognize a specific target, to conjugate drugs, nanoparticles or nucleic acid therapeutics (NATs) and to cross the blood brain barrier. In this review, we summarized the main advantages of aptamers as delivery system, focusing our attention on aptamer-mediated delivery of therapeutic oligonucleotides in glioblastoma. Glioblastoma represents the most common and aggressive primary malignant brain tumor in adults, with a median survival ranging from 14.6 to 20.5 months. Currently, the standard treatment of newly diagnosed tumor includes surgical resection followed by radiotherapy and chemotherapy with the alkylating agent temozolomide. However, the overall efficacy is limited and most patients relapse within a few months, calling attention on the development of alternative therapeutic strategies. Particularly, we discussed research studies on NAT delivery mediated by aptamer chimeras and aptamer-nanoparticle complexes able to impair various processes involved in glioblastoma tumorigenesis. This overview will help to highlight how aptamers, thanks to their advantages, could represent a promising tool for the development of innovative therapeutic approaches for glioblastoma treatment.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102485"},"PeriodicalIF":5.0,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"9-Deazaadenosine directly binds PYCR1 and inhibits cancer cell proliferation through disruption of NAD+ metabolism","authors":"Jongtae Roh ,&nbsp;Inho Ahn ,&nbsp;Jong-Ryoo Choi ,&nbsp;Sung-Kyun Ko","doi":"10.1016/j.tranon.2025.102478","DOIUrl":"10.1016/j.tranon.2025.102478","url":null,"abstract":"<div><div>Cancer cells exhibit abnormal proliferation and dysregulated cell cycle checkpoints. Therefore, discovering cell cycle inhibitors is a promising strategy for cancer treatment. The pyrroline-5-carboxylate reductase 1 (PYCR1) is a key enzyme that controls proline metabolism by regulating the conversion of pyrroline-5-carboxylate to proline. PYCR1 is highly expressed in various cancers, including colon cancer. In this study, we discovered a novel role of 9-deazaadenosine (9-DAA) as a cell cycle inhibitor and demonstrated that this compound directly binds to PYCR1. Our results suggest that the inhibitory effects of 9-DAA are due to nicotinamide adenine dinucleotide. We further demonstrated that PYCR1 was elevated under hypoxia and in 3D spheroids in colon cancer and that 9-DAA effectively inhibited cancer progression under cancer-mimicking conditions and in vivo.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102478"},"PeriodicalIF":5.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MetInfilt: A prospective trial highlighting the importance of the histological growth pattern in brain metastases","authors":"Martin A. Proescholdt ,&nbsp;Tommaso Araceli ,&nbsp;Karl-Michael Schebesch ,&nbsp;Christian Doenitz ,&nbsp;Christina Wendl ,&nbsp;Katja Evert ,&nbsp;Ekaterina Noeva ,&nbsp;Julius Hoehne ,&nbsp;Markus J. Riemenschneider ,&nbsp;Daniela Hirsch ,&nbsp;Nils Ole Schmidt ,&nbsp;Daniela Sparrer ,&nbsp;Florian Lüke ,&nbsp;Daniel Heudobler ,&nbsp;Tobias Pukrop ,&nbsp;Raquel Blazquez","doi":"10.1016/j.tranon.2025.102480","DOIUrl":"10.1016/j.tranon.2025.102480","url":null,"abstract":"<div><h3>Background</h3><div>While the histological growth pattern (HGP) of liver metastases is frequently evaluated, the same attention is often absent for brain metastases despite evidence suggesting its prognostic significance. This oversight may stem from the lack of a standardized method for assessing the HGP at the macro-metastasis / brain parenchyma interface (MMPI_brain). MetInfilt is the first prospective, imaging-guided trial aimed at standardizing the collection and analysis of the HGP at the MMPI_brain.</div></div><div><h3>Methods</h3><div>We recruited fifty patients. The MMPI_brain was identified using preoperative contrast-enhanced T1-weighted MRI. Intraoperative confocal microscopy (CONVIVO) visualized the MMPI_brain, while a YELLOW 560 nm filter in the surgical microscope facilitated precise tissue sampling. Samples from the MMPI_brain and the core of the metastasis were collected for postoperative histological confirmation.</div></div><div><h3>Results</h3><div>The protocol achieved successful tissue acquisition from the MMPI_brain in 93.2 % of patients, meeting the study's primary endpoint. Preoperative MRI patterns strongly correlated with infiltrative HGPs, and CONVIVO accurately visualized the MMPI_brain intraoperatively. Exploratory analyses suggest that infiltrative HGPs might negatively impact patient prognosis and represent a potential risk of meningeal metastasis.</div></div><div><h3>Conclusions</h3><div>Our neurosurgical protocol allows the successful and precise acquisition of tissue from the MMPI_brain through presurgical imaging, intraoperative microscopy, and fluorescence-assisted sampling. The evaluation of the HGP in our limited patient cohort highlights its potential clinical significance and supports the urgent necessity to investigate it further for the benefit of patients with brain metastases.</div></div><div><h3>Clinical trial registration number</h3><div>Z-2019–1307–9.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102480"},"PeriodicalIF":5.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanded and activated marrow-infiltrating lymphocytes exhibit potent antimyeloma activity against autologous multiple myeloma cells","authors":"Seo-Yeon Ahn ,&nbsp;Manh-Cuong Vo ,&nbsp;Van-Tan Nguyen ,&nbsp;Van-Dinh-Huan Tran ,&nbsp;Tien Nguyen Duc ,&nbsp;Mihee Kim ,&nbsp;Ga-Young Song ,&nbsp;Jae-Sook Ahn ,&nbsp;Deok-Hwan Yang ,&nbsp;Hyeoung-Joon Kim ,&nbsp;Sung-Hoon Jung ,&nbsp;Je-Jung Lee","doi":"10.1016/j.tranon.2025.102475","DOIUrl":"10.1016/j.tranon.2025.102475","url":null,"abstract":"<div><div>Adoptive immunotherapy represents a promising treatment for multiple myeloma (MM), relying on the availability of sustainable tumor-specific cytotoxic T cells. This study generated potent <em>ex vivo</em> expanded and activated marrow-infiltrating lymphocytes (eMILs) from MM patients and evaluated their immunologic characteristics and cytotoxic potential. MILs were expanded using anti-CD3/CD28 beads in the presence of IL-2, IL-7, and IL-15. The expansion rate, proportions of effector cells (including CD4⁺ <em>T</em> cells, CD8⁺ <em>T</em> cells, natural killer cells, and memory T cells), and the functional capacity of eMILs were assessed over 2 weeks of culture. Co-culturing MILs with anti-CD3/CD28 beads and cytokines resulted in substantial expansion and activation of MILs during the 14-day culture period. The eMILs displayed an increased proportion of CD8⁺ <em>T</em> cells and a high prevalence of central memory T cells (Tcm; &gt; 80 %), with minimal presence of myeloid-derived suppressor cells or regulatory T cells. Compared to expanded peripheral blood lymphocytes, eMILs demonstrated potent cytotoxicity against target MM cells, particularly CD138⁺ primary MM cells from autologous patients. These findings suggest that MILs derived from the bone marrow (BM) of MM patients can be expanded and activated to exhibit enhanced antigen specificity for CD138⁺ MM cells. Furthermore, eMILs may induce sustained cytotoxic effects due to their high proportion of Tcms. In conclusion, as a unique subset of T cells shaped by the BM microenvironment, MILs show promise as a novel immunotherapeutic approach for MM.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102475"},"PeriodicalIF":5.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144702463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the heterogeneity of pancreatic ductal adenocarcinoma","authors":"Juan Iovanna ,&nbsp;Nicolas Fraunhoffer ,&nbsp;Raul Urrutia ,&nbsp;Nelson Dusetti","doi":"10.1016/j.tranon.2025.102479","DOIUrl":"10.1016/j.tranon.2025.102479","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, treatment-resistant cancer characterized by extensive inter- and intra-tumoral heterogeneity. Although over 95 % of cases harbor KRAS mutations and commonly altered tumor suppressors like TP53, SMAD4, and CDKN2A, these genetic changes alone do not fully explain PDAC variability. We propose a paradigm shift: PDAC heterogeneity is not solely genetic but also shaped by epigenetic regulation and the tumor microenvironment. Traditional transcriptomic classifications define PDAC into fixed subtypes, primarily classical and basal-like, but we argue these are not static categories. Instead, PDAC phenotypes exist along a dynamic continuum influenced by stromal interactions and epigenetic cues. This model challenges the binary classification view. We show that transitions from classical to basal-like states are gradual and reversible, driven by tumor-stroma crosstalk and chromatin remodeling. Such plasticity underpins tumor adaptation, resistance, and progression. Embracing this dynamic framework offers novel therapeutic opportunities.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102479"},"PeriodicalIF":5.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AGEs-RAGE manipulates tumor intrinsic pERK/Sp1/IL6 pathway and reprograms macrophage to promote intrahepatic cholangiocarcinoma progression","authors":"Juan Zhang ,&nbsp;Biyang Jing ,&nbsp;Xiaojian Ni ,&nbsp;Youpei Lin ,&nbsp;Jiaomeng Pan ,&nbsp;MaoPei Chen ,&nbsp;Boheng Zhang ,&nbsp;Lan Zhang ,&nbsp;Ningling Ge ,&nbsp;Ruyuan Deng ,&nbsp;Xiao Wang ,&nbsp;Guohe Song","doi":"10.1016/j.tranon.2025.102446","DOIUrl":"10.1016/j.tranon.2025.102446","url":null,"abstract":"<div><div>Tumors often exhibit oxygen deprivation and enhanced glucose uptake, leading to glycolysis. Advanced glycation end products (AGEs) protein modifications induced by hyperglycemia—activate signaling pathways that promote cancer progression upon binding to its receptor (RAGE). In this study, AGEs-treatment enhanced the growth, invasion and migration of intrahepatic cholangiocarcinoma cells (ICC), while increasing IL-6 expression and secretion. Meanwhile, AGEs stimulated the expression of RAGE, specificity protein 1 (Sp1), and the phosphorylation of extracellular signal-regulated kinase (ERK) in a dose-dependent manner. However, these effects were attenuated by RAGE antibody blockade, RAGE knockdown, the ERK inhibitor U0126, or Sp1-specific siRNA. Furthermore, the supernatant of AGEs-treated RBE cells induced M2 polarization of THP-1 macrophages. Thus, AGEs promote ICC progression partly through the pERK/Sp1/IL-6 pathway and M2 macrophage polarization. These findings highlight underscore the role of the AGEs-RAGE axis in driving ICC progression via pERK/Sp1/IL-6 signaling.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"60 ","pages":"Article 102446"},"PeriodicalIF":5.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}