Translational Oncology最新文献

{"title":"Erianin ameliorates morphine tolerance and glioma progression through the JAK2-STAT3 pathway","authors":"Yi Gu ,&nbsp;Jin Xu ,&nbsp;Xiaoli Ding ,&nbsp;Su Wan ,&nbsp;Fuying Cai ,&nbsp;Hai Qin","doi":"10.1016/j.tranon.2025.102551","DOIUrl":"10.1016/j.tranon.2025.102551","url":null,"abstract":"<div><div>Prolonged morphine use and glioma-induced stress have a significant impact on pain management outcomes and tumor progression. This study investigates Erianin’s potential to alleviate morphine tolerance and inhibit glioma progression through its modulation of the JAK2/STAT3 pathway. Glioma-bearing morphine-tolerant mouse models were used to evaluate Erianin’s effects on analgesia, tumor growth, and molecular pathways. Erianin administration effectively reduced morphine tolerance (50 % inhibition rate) and glioma progression (60 % inhibition rate) by inhibiting the JAK2/STAT3 signaling and suppressing BDNF expression in dorsal root ganglia (DRG). Multi-omics analysis (integrating transcriptomics and miRNA-seq data) highlighted key roles of miR-375 and miR-20a in targeting JAK2, demonstrating their critical involvement in regulating morphine tolerance and glioma-induced neuroinflammation. Further, chronic morphine use was identified as modulators of the JAK2-STAT3 pathway dysregulation. These findings uncover the potential of Erianin as a therapeutic agent. Specifically, we reveal druggable targets within inflammatory signaling cascades, providing molecular blueprints for precision interventions in pain-related oncology care.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102551"},"PeriodicalIF":5.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201401","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":"Expression of ORMDL1 in esophageal squamous cell carcinoma and its effect on patient outcomes: A potential biomarker and treatment target","authors":"Hao Wang ,&nbsp;Weisong Zhang ,&nbsp;Yihao Wang ,&nbsp;Rongqi Guo ,&nbsp;Yeting Li ,&nbsp;Zhongquan Yi ,&nbsp;Song Yan ,&nbsp;Xia Li ,&nbsp;Jianxiang Song","doi":"10.1016/j.tranon.2025.102554","DOIUrl":"10.1016/j.tranon.2025.102554","url":null,"abstract":"<div><div>ORMDL1, a member of the ORMDL protein family, is an endoplasmic reticulum membrane protein. Abnormal expression of ORMDL1 in various types of human cancers has attracted much attention in recent years. However, the function of ORMDL1 in ESCC has not been reported. The present study was the first to report that ORMDL1 can serve as a useful prognostic marker in ESCC. The methods used to assess the role of ORMDL1 in predicting the prognosis of ESCC were mainly bioinformatics analysis, WB and Immunohistochemistry. The abnormal expression of ORMDL1 in various types of cancers was determined using data from TCGA and GEO databases. In ESCC, we found that the expression level of ORMDL1 was significantly higher in tumor tissues than that in normal esophageal tissues (<em>p</em> &lt; 0.001). The association between high level of ORMDL1 expression and poor prognosis was evaluated with Kaplan-Meier survival analysis. Univariate and multivariate Cox regression analyses were performed on both TCGA and our own samples to determine whether ORMDL1 is an independent prognostic factor for ESCC. Moreover, analysis of immune infiltration showed a significant connection between ORMDL1 expression and various immune cell subtypes, including T helper cells and neutrophils, underscoring its potential as a biomarker for poor prognosis. Western blot analysis further validated that the expression levels of ORMDL1 in esophageal squamous cell carcinoma (ESCC) tissues and cell lines are significantly greater compared to those in normal esophageal tissues and epithelial cell lines. This finding aligns with the outcomes observed in database analyses. By integrating multi-omics data with experimental findings from clinical samples, we hypothesize that ORMDL1 may contribute to the initiation and advancement of ESCC. Its elevated expression is not only associated with unfavorable prognosis but may also be involved in tumor immune evasion through its impact on the tumor immune microenvironment. Consequently, ORMDL1 has the potential to act as a promising molecular biomarker for diagnosing and assessing prognosis in ESCC, offering new avenues for research and targets for personalized therapies for ESCC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102554"},"PeriodicalIF":5.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207688","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":"Proteomic landscape of colorectal cancer liver metastasis","authors":"Ju Wu ,&nbsp;Linlin Liu ,&nbsp;Yaoyuan Chang ,&nbsp;Xiaoyu Duan ,&nbsp;Xi Chen ,&nbsp;He Li ,&nbsp;Zheng Wang ,&nbsp;Lianyi Guo ,&nbsp;Jiajun Yin","doi":"10.1016/j.tranon.2025.102558","DOIUrl":"10.1016/j.tranon.2025.102558","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancer metastasis, especially liver metastasis, is characterized by significant intricate diversity and remains a major contributor to patient mortality. Despite its clinical importance, the precise molecular mechanisms driving metastasis remain poorly understood.</div></div><div><h3>Methods</h3><div>To investigate the molecular drivers of metastasis heterogeneity, we performed a comprehensive proteomic analysis of non-metastatic (NM) colorectal cancer tissues, as well as metachronous (MM) and synchronous (SM) metastatic tissues.</div></div><div><h3>Results</h3><div>Our analysis revealed distinct biological features associated with colorectal cancer liver metastasis. Notably, we identified P53-mediated hyperproliferation as a common initiating factor in the occurrence of CRC. Additionally, metabolic dysregulation emerged as a key hallmark of CRC liver metastasis. Importantly, MM tumors exhibited suppressed ferroptosis and activation of the TGF-β signaling pathway, while SM tumors displayed inhibited anoikis and activation of the WNT signaling pathway, accompanied by activated angiogenesis. Most strikingly, CEACAM6 was identified as the only protein exhibiting a stepwise decrease in expression from NM to MM and further to SM, underscoring its unique role in metastatic progression.</div></div><div><h3>Conclusions</h3><div>These findings provide new insights into the molecular complexities underpinning colorectal cancer liver metastasis. Our identification of CEACAM6 as a differential marker highlights its potential as a diagnosis marker and therapeutic target, offering new avenues for the treatment of metastatic CRC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102558"},"PeriodicalIF":5.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201456","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":"TCEB2 promotes M2 polarization of macrophages in triple negative breast cancer by mediating ubiquitination degradation of Slit2 through recruiting NEDD4","authors":"Li Liu ,&nbsp;Wang Xiao ,&nbsp;Jie Zeng ,&nbsp;Jianing Yi ,&nbsp;Haoli Gong ,&nbsp;Luyao Liu","doi":"10.1016/j.tranon.2025.102536","DOIUrl":"10.1016/j.tranon.2025.102536","url":null,"abstract":"<div><h3>Background</h3><div>M2-polarized tumor-associated macrophage infiltration is a key risk factor for poor prognosis in triple-negative breast cancer (TNBC). This study investigated the role of transcription elongation factor B polypeptide 2 (TCEB2) in regulating M2 macrophage polarization during TNBC development.</div></div><div><h3>Methods</h3><div>The expression of gene or protein was tested by qRT-PCR, western blot, and IHC. CCK8, colony formation, wound healing, and Transwell assays were used to evaluate TNBC cell malignant behaviors, including cell viability, proliferation, migration, and invasion. The secretion levels of cytokines were detected by ELISA. Ubiquitin-based IP assays were used to detect Slit2 ubiquitination. The combined relation between TCEB2, Slit2, and NEDD4 was investigated using Co-IP assay.</div></div><div><h3>Results</h3><div>Our results demonstrated that M2 macrophage polarization was activated in TNBC, which might be related to TCEB2 upregulation. TCEB2 knockdown reduced TNBC cell growth, migration, invasion, and their ability to induce M2 macrophage polarization. Mechanistically, TCEB2 mediated Slit2 K63 ubiquitination degradation in TNBC by interacting with NEDD4. As expected, the inhibitory effect of TCEB2 silencing on the ability of TNBC cells to induce M2 macrophage polarization was reversed by Slit2 knockdown. Finally, TCEB2 knockdown inhibited TNBC tumor growth and TNBC-induced M2 macrophage polarization <em>in vivo</em>.</div></div><div><h3>Conclusion</h3><div>TCEB2 upregulation promoted TNBC-induced M2 macrophage polarization to accelerate TNBC development by mediating Slit2 K63-ubiquitination degradation through interacting with NEDD4.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102536"},"PeriodicalIF":5.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145160090","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":"Near-infrared spectroscopy of blood plasma amino acids with chemometrics towards breast cancer discrimination","authors":"Liying Zhu ,&nbsp;Haizhi Li ,&nbsp;Wen Qian ,&nbsp;Chengcheng Li ,&nbsp;Changyudong Huang ,&nbsp;Yiqiong Zhang ,&nbsp;Yunfeng Duan ,&nbsp;Shuang Wang ,&nbsp;Yongjie Xu ,&nbsp;Jingzhi Zhang ,&nbsp;Mi Liu ,&nbsp;Xing Li ,&nbsp;Shuyun Zhao ,&nbsp;Wei Pan","doi":"10.1016/j.tranon.2025.102542","DOIUrl":"10.1016/j.tranon.2025.102542","url":null,"abstract":"<div><div>Breast cancer (BC) is the most prevalent cancer type in women worldwide. BC cells need more amino acids to meet the demands of rapid proliferation. The present study focused on the role of near-infrared (NIR) spectroscopy in analyzing blood plasma samples of patients with BC to differentiate them from healthy controls. The possibility of quantitative detection of 20 amino acids in BC plasma by NIR spectroscopy was investigated. A total of 180 samples (from 80 patients with BC, 30 patients with benign breast disease and 70 healthy controls) were analyzed. Canonical correlation analysis was used to analyze the relationship between clinical biochemical parameters and the amino acid metabolic profile of patients with BC. In the study, plasma glutamine, histidine, threonine, proline and phenylalanine content of patients with BC was higher than that in plasma from healthy controls (P&lt;0.05) based on NIR spectroscopy. There was an overall correlation (r=0.935) between three clinical parameters (age, albumin and total triglyceride) and four amino acids (glutamic acid, tyrosine, valine and lysine) in patients with BC. In this study, a quantitative and qualitative model was constructed, and this was used to detect plasma amino acids of patients with BC using NIR spectroscopy with good performance. It fully demonstrated the potential and advantages of NIR spectroscopy combined with chemometrics in BC research, which can provide a novel research strategy and technical platform for the study of plasma amino acid metabolism of BC and provide basic experimental for the clinical diagnosis and treatment of BC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102542"},"PeriodicalIF":5.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110009","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":"Camizestrant causes reversible pharmacological effects on retinal responses in rats","authors":"Gregory Hamm ,&nbsp;Gareth Maglennon ,&nbsp;Stuart Purbrick ,&nbsp;Lucy Flint ,&nbsp;Glen Hawthorne ,&nbsp;James Atkinson ,&nbsp;Ruth Macdonald ,&nbsp;Alexander Harmer ,&nbsp;Stewart Jones ,&nbsp;Yelena Krakova ,&nbsp;James Ver Hoeve ,&nbsp;Andrew Walding ,&nbsp;Lindsay Wright","doi":"10.1016/j.tranon.2025.102539","DOIUrl":"10.1016/j.tranon.2025.102539","url":null,"abstract":"<div><div>Some patients treated with camizestrant in the SERENA-1 and SERENA-2 clinical trials experienced mild, transient, reversible visual effects. This nonclinical investigation used electroretinograms (ERGs) and mass spectrometry imaging to examine the effect of camizestrant on retinal responses in rats and to investigate the origin of the visual effects observed in humans.</div><div>Mass spectrometry imaging was used to confirm the presence of camizestrant in the retina of rats following 7 consecutive days of dosing (75 mg kg^-1/day). A separate group of rats then received doses of either camizestrant (5, 12, 25, or 75 mg kg^-1/day) or control over 7 consecutive days. They were observed for 7 additional days without further dosing. ERGs were conducted at baseline, Days 1 and 7, and 7 days after last dose to assess changes in retinal responses. Ophthalmic examinations were conducted pre-dose and on Days 8 and 15.</div><div>Administration of camizestrant at ≥12 mg kg^-1/day significantly reduced dark-adapted ERG b-waves and oscillatory potential amplitudes, increased light-adapted b-wave amplitude and latency, and reduced the rate of light adaptation. All observed effects were dose dependent and reversible, returning to baseline levels a week after post-dose washout. There was no evidence of any structural changes in the eye.</div><div>The results support a reversible, pharmacological effect of camizestrant on retinal responses in the absence of structural changes and are consistent with clinical findings. These data offer insight into the potential mechanism of the visual effects observed in patients.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102539"},"PeriodicalIF":5.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110010","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":"Extracellular vesicles as biomarkers for endometrial cancer – A systematic review","authors":"Eva Baxter ,&nbsp;Soumyalekshmi Nair ,&nbsp;Zoe West ,&nbsp;Carlos Salomon ,&nbsp;Andreas Obermair","doi":"10.1016/j.tranon.2025.102543","DOIUrl":"10.1016/j.tranon.2025.102543","url":null,"abstract":"<div><h3>Background</h3><div>The current method for diagnosing endometrial cancer and monitoring treatment response is invasive and fraught with both interobserver and intraobserver variability. Less invasive and more reproducible methods are desirable. This systematic review examines the evidence for extracellular vesicles as minimally invasive biomarkers for endometrial cancer.</div></div><div><h3>Methods</h3><div>PubMed, Embase and Web of Science were searched for studies reporting extracellular vesicles as biomarkers in females with endometrial cancer. Risk of bias was assessed using the QUADAS-2 tool. A descriptive synthesis of biomarkers reported in the included studies was conducted.</div></div><div><h3>Results</h3><div>Of the 680 unique records reviewed, 23 studies were included. All 23 studies investigated extracellular vesicles as diagnostic biomarkers. Ten extracellular vesicle-associated biomarkers were consistently reported to be differentially abundant between endometrial cancer cases and controls in multiple independent studies and hence may be putative diagnostic biomarkers. Levels of extracellular vesicles, LGALS3BP (galectin 3 binding protein), miR-15a-5p, and miR-21–3p were elevated, while levels of miR-26a-5p, miR-130a-3p, miR-139, miR-219a-5p, miR-222–3p, and miR-885 were decreased in endometrial cancer cases versus controls. Seven studies also investigated extracellular vesicles as prognostic biomarkers, but no biomarker was reported as prognostic in more than one study.</div></div><div><h3>Conclusion</h3><div>Of the ten putative diagnostic biomarkers, extracellular vesicle-associated miR-21–3p, miR-26a-5p, miR-130a-3p, miR-139 and miR-219a-5p are the most promising as their expression in extracellular vesicle preparations appears to reflect that in endometrial tissue. However, there are significant concerns regarding study quality, limited adherence to consensus recommendations on extracellular vesicle research and lack of evidence supporting biomarkers being encapsulated within extracellular vesicles.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102543"},"PeriodicalIF":5.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110008","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":"The protective role of IL-17C in oral squamous cell carcinoma","authors":"Zivile Giedraityte ,&nbsp;Joosua Suominen ,&nbsp;Wafa Wahbi ,&nbsp;Ahana Kapuge Dona Varuni Yashodha Ratnayake ,&nbsp;Tuulia Onali ,&nbsp;Martina Giacomini ,&nbsp;Sami Kilpinen ,&nbsp;Katja Korelin ,&nbsp;Maija Risteli ,&nbsp;Tuula Salo ,&nbsp;Ahmed Al-Samadi","doi":"10.1016/j.tranon.2025.102541","DOIUrl":"10.1016/j.tranon.2025.102541","url":null,"abstract":"<div><h3>Background</h3><div>Oral squamous cell carcinoma (OSCC) is a common cancer characterised by high rates of metastasis and mortality. Interleukin‑17C (IL-17C) is expressed by several cell types, including epithelial cells, and signals through the heterodimeric IL-17RE/IL-17RA receptor complex at various mucosal sites. The role of IL-17C in OSCC development and progression remains unexamined; therefore, this study aimed to elucidate its potential involvement.</div></div><div><h3>Methods</h3><div>Among 11 OSCC cell lines, OU-OTSCC-7B and UH-SCC-17B exhibited a high transcript expression of IL-17C receptors (IL-17RE and IL-17RA) and were selected for further assays. Proliferation, apoptosis, migration, and invasion assays were conducted in the presence and absence of IL-17C. Using a zebrafish xenograft model, we assessed the <em>in vivo</em> effects of IL-17C. Additionally, we performed RNA sequencing after stimulating UH-SCC-17B cells with IL-17C.</div></div><div><h3>Results</h3><div>IL-17C significantly inhibited the proliferation and migration of UH-SCC-17B cells, but had no effect on OU-OTSCC-7B cells. Moreover, IL-17C reduced the tumour size of UH-SCC-17B cells by approximately 10% in the zebrafish model. RNA sequencing revealed the downregulation of five genes, three of which were mitochondrial genes—MT-CYB, MT-ND1, and MTND2P28—implicated in cancer progression. Gene set enrichment analysis revealed the enrichment of the MYC target and oxidative phosphorylation gene sets following IL-17C treatment.</div></div><div><h3>Conclusions</h3><div>IL-17C appears to play a protective role in some OSCC cells. While this study indicates the potential of using IL-17C as a therapeutic candidate for OSCC patients, its relatively mild and selective effect suggests it may be more effective as part of a combination therapy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102541"},"PeriodicalIF":5.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103004","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":"Genetic associations of cholelithiasis and biliary tract cancer","authors":"Yong Jiang ,&nbsp;Huimou Chen ,&nbsp;Qing Tian ,&nbsp;Chonghui Hu ,&nbsp;Zhengyu Wu ,&nbsp;Yuan Yuan ,&nbsp;Xueliang Ouyang ,&nbsp;Kunlong Chang ,&nbsp;Daixin Wu ,&nbsp;Juncheng Chen ,&nbsp;Junwei Huang ,&nbsp;Rufu Chen ,&nbsp;Shangyou Zheng ,&nbsp;Li Li","doi":"10.1016/j.tranon.2025.102533","DOIUrl":"10.1016/j.tranon.2025.102533","url":null,"abstract":"<div><div>Biliary tract cancer (BTC) is highly malignant and more prevalent in populations with cholelithiasis, but the underlying mechanisms remain unclear. This study aimed to investigate the potential genetic links between cholelithiasis and BTC. We first employed single- and two-sample Mendelian randomization to assess whether the association between cholelithiasis and BTC incidence was influenced by confounding factors, revealing a significant association between cholelithiasis and BTC (<em>P</em> &lt; 0.05). Multi-trait analysis of GWAS identified five novel lead genomic risk loci for BTC, with functional mapping and annotation performed using FUMA. Colocalization analysis using quantitative trait loci data highlighted shared signals for LRPPRC and ABCG5 in liver tissue. Additionally, in individuals without cholelithiasis, genetic loci rs6741243 and rs7599981 were associated with an increased BTC risk (both <em>P</em> &lt; 0.05) in a Cox regression model. Gene expression analysis further supported these findings, showing significant upregulation of LRPPRC (<em>P</em> &lt; 0.001) and downregulation of ABCG5 (<em>P</em> &lt; 0.001) in BTC tissues, confirming their roles in carcinogenesis. This study provides compelling evidence for a genetic association between cholelithiasis and BTC, highlighting the role of genetic variants in ABCG5/8 and LRPPRC in mediating these conditions.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102533"},"PeriodicalIF":5.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102990","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":"The KRAS-G12D mutation drives venous thromboembolism (VTE) and colorectal cancer progression via MAPK/ERK signaling","authors":"Jieqi Mao ,&nbsp;Xu Ming ,&nbsp;Mei Wang ,&nbsp;Yichao Du ,&nbsp;Yang Shen ,&nbsp;Dapeng Li ,&nbsp;Ziyan Zhu ,&nbsp;Xu Li ,&nbsp;Jikun Li","doi":"10.1016/j.tranon.2025.102529","DOIUrl":"10.1016/j.tranon.2025.102529","url":null,"abstract":"<div><h3>Objective</h3><div>KRAS mutations occur in nearly 50 % of colorectal cancer (CRC) cases, with G12D representing the most frequent variant. While CRC is recognized as a moderate risk factor for venous thromboembolism (VTE), the thrombogenic potential of KRAS-G12D mutations remains poorly understood.</div></div><div><h3>Methods</h3><div>We established a KRAS-G12D-associated coagulation gene (KMCG) prognostic model through integrative analysis of clinical data from CRC patients. Mechanistic investigations combining in vitro and in vivo models revealed that KRAS-G12D potentiates thrombotic risk through MAPK/ERK pathway activation.</div></div><div><h3>Results</h3><div>Integrating TCGA data, we constructed a KRAS-G12D-associated coagulation gene (PLCG2/MAPK12/C4B)-based prognostic model, where high-risk patients exhibited significantly reduced overall survival (HR=3.44) and superior 1-year AUC (0.718). Mechanistic profiling revealed high-risk enrichment in coagulation cascades, MAPK signaling, and immune infiltration, coupled with elevated tumor mutational burden (TMB) and immunotherapy sensitivity. Clinical validation confirmed KRAS-G12D mutation markedly increased D-dimer levelsand VTE incidence. Functional studies demonstrated mutant-driven platelet hyperactivation via MAPK/ERK pathway activation, evidenced by elevated aggregation rates and procoagulant endothelial transformation. In vivo, MAPK/ERK inhibitor U0126 attenuated thrombosis and metastasis, validating the pathway’s dual role in thrombogenesis and tumor progression.</div></div><div><h3>Conclusion</h3><div>Our findings establish KMCG as a novel biomarker integrating thrombotic risk and tumor progression, while mechanistically linking KRAS-G12D-driven MAPK activation to both cancer metastasis and thrombosis. This dual regulatory axis provides therapeutic targets for simultaneously managing thrombotic complications and malignant progression in KRAS-mutant CRC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"62 ","pages":"Article 102529"},"PeriodicalIF":5.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092605","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}