Molecular Carcinogenesis最新文献

{"title":"Therapeutic Suppression of Triple-Negative Breast Cancer via Pachymic Acid-Induced KIF18B Inhibition and Ferroptosis Activation.","authors":"Tao Huang, Jizong Zhang","doi":"10.1002/mc.70045","DOIUrl":"https://doi.org/10.1002/mc.70045","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is a particularly aggressive malignant tumor. Pachymic acid (PA), a bioactive triterpenoid, has demonstrated multi-target therapeutic effects in TNBC. However, the detailed molecular networks responsible for its anti-TNBC effects have not yet been fully elucidated. The therapeutic potential of PA was evaluated by measuring cell viability, proliferation, invasion, and migration. The impact on ferroptosis was assessed by detecting ROS, MDA, GSH, and Fe2⁺ levels. Animal xenograft experiments were used to analyze the role in vivo. Expression analysis was performed using immunoblot, quantitative PCR, and immunohistochemical assays. PA exhibited antiproliferative, anti-migratory, and anti-invasive effects on BT-549 and MDA-MB-231 cells in vitro. PA induced oxidative stress and triggered ferroptosis in BT-549 and MDA-MB-231 cells. Kinesin family member 18B (KIF18B) was overexpressed in TNBC and was reduced by PA treatment. KIF18B restoration counteracted PA-mediated antiproliferative, anti-migratory, anti-invasive, and pro-ferroptosis effects on BT-549 and MDA-MB-231 cells. Furthermore, restored expression of KIF18B attenuated the efficacy of PA in reducing xenograft growth in vivo. Our study demonstrates that PA suppresses TNBC progression by inducing ferroptosis and inhibiting malignant phenotypes through KIF18B downregulation, offering experimental evidence supporting the clinical potential of PA as a novel therapeutic agent for TNBC treatment.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244835","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":"Helicobacter pylori Infection, Metabolomic Signature and Extra-gastric Cancer Risk: A Mediation and Mendelian Randomization Analysis.","authors":"Yan Chen, Yuhui Yu, Qiufen Sun, Xia Zhu, Lijun Bian, Qian Gao, Zhe Li, Xinxiang Gao, Qian Li, Jiaying Gu, Xin Fang, Yunfei Wang, Aiping Zhang, Dong Hang, Guangfu Jin, Caiwang Yan","doi":"10.1002/mc.70050","DOIUrl":"https://doi.org/10.1002/mc.70050","url":null,"abstract":"<p><p>Emerging evidence suggests that Helicobacter pylori (H. pylori) infection may contribute to extra-gastric malignancies, but the mechanisms are unclear. Using untargeted metabolomics data from two prospective Chinese cohorts, we constructed an H. pylori associated metabolomic signature in 1800 baseline participants and evaluated cancer risks using conditional logistic regression in 1:1 matched case-control studies for lung cancer (n = 352 pairs), colorectal cancer (CRC; n = 190 pairs), esophageal cancer (n = 146 pairs), and hepatocellular carcinoma (n = 163 pairs), with confounder adjustment and sex stratification. Mediation analysis was performed to evaluate the mediating effects of the metabolomic signature and specific plasma metabolites on the observed associations. Mendelian randomization (MR) analysis was conducted to evaluate causal relationships. H. pylori infection was significantly associated with an increased risk of CRC (OR = 1.80, 95% CI: 1.13-2.85), especially driven by males (OR = 3.01, 95% CI: 1.44-6.31), but not with other cancers. Additionally, the H. pylori infection-related metabolomic signature consisting of 26 metabolites (OR per standard deviation [SD] increment = 1.52, 95% CI: 1.03-2.25) and plasma metabolite methionine sulfone (OR per SD increment = 1.73, 95% CI: 1.16-2.58) were positively associated with CRC risk in males. Mediation analysis indicated partial mediation by the metabolomic signature (12.08%, 95% CI: 0.26-46.88%) and methionine sulfone (16.79%, 95% CI: 0.11-74.76%). MR analysis further supported a potentially causal association between methionine sulfone and CRC (OR = 1.08, 95% CI: 1.02-1.15). Collectively, these results implicate sex-specific metabolomic alterations, particularly involving methionine sulfone, in mediating the relationship between H. pylori infection and CRC risk in males. These insights advance understanding of CRC pathogenesis and may inform targeted prevention strategies.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244842","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":"Long Noncoding RNA MNX1-AS1 Promotes Tumorigenesis of Breast Cancer by Binding IGF2BP1 to Activate c-MET.","authors":"Jinrong Xie, Jianchun Gu, Wenjie Lv, Limin Cheng, Shuxian Chen, Ran Wu, Yan Liang, Meiling Zhu, Siyu Chen, Mawei Jiang, Jun Su","doi":"10.1002/mc.70019","DOIUrl":"10.1002/mc.70019","url":null,"abstract":"<p><p>Breast cancer is the most common malignancy that threaten women's health seriously. Many studies have shown that long noncoding RNAs can play significant role in the tumorigenesis of breast cancer. By analyzing the TCGA breast cancer genome data and transcriptome data, we found that copy number amplification drives the activation of long noncoding RNA MNX1-AS in breast cancer and indicates poor prognosis. Functionally, MNX1-AS1 could regulate pathogenesis of breast cancer in vitro and in vivo. Mechanistically, MNX1-AS1 could bind IGF2BP1, which increased the interaction of IGF2BP1 with MET mRNA to promote its stability, thus promoting tumorigenesis of breast cancer. Moreover, combination of MNX1-AS1 inhibition and MET small molecule inhibitor (PHA-665752, PHA) exhibited better antitumor efficacy in xenograft model, suggesting the therapeutic potential. Overall, our findings indicated that MNX1-AS1/MET regulatory axis may serve as a potential therapeutic target in breast cancer.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1697-1707"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708308","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 Role and Mechanism of KIAA1429-Mediated m6A Modification in Pancreatic Adenocarcinoma.","authors":"Pengbo Li, Yeting Lu, Zhen Zheng, Jiaming Lv, Jing Hu","doi":"10.1002/mc.70015","DOIUrl":"10.1002/mc.70015","url":null,"abstract":"<p><p>This study aimed to study the mechanism by which m6A methyltransferase, KIAA1429, affect pancreatic adenocarcinoma (PAAD) cell malignant behaviors in relation to N6-methyladenosine (m6A) modification. RT-qPCR, Western blot, immunohistochemistry (IHC), and m6A RNA immunoprecipitation (Me-RIP) assays were performed on PAAD tumor and adjacent non-tumor tissues (n = 39) to detect KIAA1429, AKT2 mRNA and protein levels, as well as overall tissue RNA m6A methylation levels. Tumor cells were transfected with siRNA targeting KIAA1429 (si-KIAA1429) or plasmids overexpressing AKT2 (oe-AKT2). Cell activities were assessed, followed by assessment of autophagic flux using the mRFP-GFP-LC3 reporter. In PAAD tissues and cell lines, KIAA1429 was substantially expressed. In PAAD patients, this expression was linked to a considerably lower overall and disease-specific survival rate. KIAA1429 knockdown inhibited PAAD cell malignant behaviors and promoted autophagy. Mechanistically, KIAA1429 mediated AKT2 m6A modification to enhance AKT2 mRNA stability and upregulate AKT2 expression, partially reversing the mediating effects of KIAA1429 knockdown on PAAD cell malignant behaviors and autophagy. KIAA1429 knockdown also inhibited PAAD tumor growth in vivo. KIAA1429 promotes PAAD cell malignant behaviors while inhibiting autophagy activity by mediating AKT2 m6A modification and enhancing AKT2 expression.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1667-1682"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708309","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":"KIF4A Inhibits Ferroptosis in Glioblastoma via the CHMP4B/GPX4 Axis and Promotes Temozolomide Resistance.","authors":"Xinan Shen, Honglei Cheng, Jiarong Zheng, Yihan Xia, Yongdong Li, Quanquan Guo, Zhicheng Zhang, Nanheng Yin, Yongshun Liu, Jun Dong, Yuntian Shen","doi":"10.1002/mc.70006","DOIUrl":"10.1002/mc.70006","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most malignant primary brain tumor in adults. Temozolomide (TMZ) stands for the first-line chemotherapeutic agent against GBM. TMZ resistance is an important factor contributing to the poor prognosis of GBM, but the underlying molecular mechanisms are unclear. Previous studies have suggested that KIF4A may be an indicator of poor prognosis in glioma patients, but the association of KIF4A with TMZ resistance has never been investigated. The detection of ferroptosis levels in GBM cells was accomplished through the utilization of ROS, MDA, JC-1, and Western blot analysis. The assessment of TMZ resistance was performed through the implementation of CCK8, cell cloning, and cell cycle analysis. The identification of downstream targets of KIF4A was facilitated by protein profiling and immunofluorescence. KIF4A inhibits ferroptosis in GBM cells through the CHMP4B/GPX4 axis and promotes TMZ resistance. Knockdown of KIF4A or CHMP4B sensitized GBM cells to chemotherapy. In addition, KIF4A induced epithelial-mesenchymal transition in GBM cells, which synergistically promoted TMZ resistance.The present study elucidates a novel mechanism of TMZ resistance in glioblastoma through the CHMP4B/GPX4 axis. Based on these findings, targeting KIF4A may offer a potential new strategy against GBM.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1650-1666"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708307","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":"CircLPP Activates the Wnt/β-Catenin Signaling Pathway via the miR-665/Wnt3a Axis and Promotes Proliferation and Metastasis in Colorectal Cancer.","authors":"Hong Gao, Qingguo Liu, Yuting Li, Xudong Sun, Jianquan Liu, Qihang Hu, Tao Jiang, Jun Song","doi":"10.1002/mc.70020","DOIUrl":"10.1002/mc.70020","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) are covalently closed RNA molecules that play critical roles in tumorigenesis and cancer progression, including colorectal cancer (CRC). However, the clinical significance, biological functions, and molecular mechanisms of many novel circRNAs in CRC remain poorly understood. In this study, we identified a novel circRNA, hsa_circ_0003759 (designated circLPP), which was significantly upregulated in CRC tissues. High circLPP expression correlated with malignant progression and poor prognosis in CRC patients. Functional experiments demonstrated that circLPP promoted CRC proliferation and migration both in vitro and in vivo. Mechanistically, circLPP upregulated Wnt3a expression and activated the Wnt/β-catenin signaling pathway by sponging miR-665. Our findings revealed that circLPP driven CRC progression by modulating the Wnt/β-catenin pathway, highlighting its potential as a therapeutic target for CRC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1763-1777"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144822109","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":"FBXW5 Promotes Epithelial-Mesenchymal Transition in Lung Adenocarcinoma Through the KLF13/TROAP Signaling Pathway.","authors":"Wen Wang, Shaungru Tian, Yuxin Ou, Jinsong Yang","doi":"10.1002/mc.70018","DOIUrl":"10.1002/mc.70018","url":null,"abstract":"<p><p>Epithelial-mesenchymal transition (EMT) has been shown to facilitate lung adenocarcinoma (LUAD) progress, and KLF13 inhibits tumor progression in various cancers. We intended to explore the mechanisms of KLF13 on EMT in LUAD. The biological functions (including cell viability, invasion, migration, and EMT) were checked using CCK-8, Transwell, and wound healing. The KLF13 and EMT markers levels were detected by immunohistochemistry. Interaction between KLF13 and TROAP promoter was probed by ChIP and dual luciferase reporter gene assay. The association between FBXW5 and KLF13 was verified by CoIP. RT-qPCR or Western blot was employed to check the expressions of FBXW5, KLF13, TROAP, and EMT markers. A xenograft tumor model was constructed to determine the growth of LUAD cells. KLF13 was lowly expressed in LUAD tissues and cells. KLF13 inhibited the invasion, migration, and EMT of LUAD cells. KLF13 suppressed TROAP transcription, and overexpression of TROAP reversed the inhibitory effect of KLF13 on the biological functions of LUAD cells. FBXW5 promoted KLF13 ubiquitinated degradation, and the knockdown of FBXW5 promoted KLF13 to inhibit LUAD cell progression. FBXW5 promoted KLF13 ubiquitinated degradation, which downregulated KLF13 to increase TROAP transcription, thereby facilitating EMT in LUAD.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1638-1649"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691038","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":"B4GALT3 as a Key Glycosyltransferase Gene in Multiple Myeloma Progression: Insights From Bioinformatics, Machine Learning, and Experimental Validation.","authors":"Apeng Yang, Mengying Ke, Lin Feng, Ye Yang, Junmin Chen, Zhiyong Zeng","doi":"10.1002/mc.70013","DOIUrl":"10.1002/mc.70013","url":null,"abstract":"<p><p>Glycosylation abnormalities are critical in the progression of various cancers. However, their role in the onset and prognosis of multiple myeloma (MM) remains underexplored. This study aims to identify glycosyltransferase (GT)-related biomarkers and investigate their underlying mechanisms in MM. GT-related genes were extracted from the MMRF-CoMMpass and GSE57317 data sets. Potential biomarkers were identified using Cox regression and Lasso analyses. A glycosyltransferase-related prognostic model (GTPM) was developed by evaluating 113 machine learning algorithm combinations. The expression of B4GALT3, a key gene identified through this model, was analyzed in MM bone marrow samples using immunohistochemistry, quantitative PCR, and Western blot. Functional roles of B4GALT3 in MM cell behavior were assessed through knockdown experiments, and its mechanism of action was investigated. The GTPM stratified MM patients into high- and low-risk groups, with significantly better survival in the low-risk group (HR = 55.94, 95% CI = 40.48-77.31, p < 0.001). The model achieved AUC values of 0.98 and 0.99 for 1- and 3-year overall survival, outperforming existing gene signatures (including EMC92, UAMS70, and UAMS17). B4GALT3 expression was significantly elevated in advanced MM stages (p < 0.001) and correlated with poorer survival. Knockdown of B4GALT3 reduced MM cell proliferation, invasion, and increased apoptosis. Mechanistic analyses revealed that B4GALT3 modulates MM cell behavior via the Wnt/β-catenin/GRP78 pathway, primarily by regulating endoplasmic reticulum (ER) stress. This study developed a novel GTPM for predicting survival in MM and identified B4GALT3 as a key gene influencing disease progression. Experimental evidence highlights B4GALT3's role in modulating ER stress and Wnt/β-catenin pathways, positioning it as a potential prognostic biomarker and therapeutic target in MM.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1595-1608"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626747","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":"Combined Inhibition of XPO1 and DNA Methylation Exerts Synergistic Effects in DLBCL.","authors":"Qi Li, Xiaofeng Xue, Si Chen, Xinyun Zhang, Yuchen Zhang, Ruijing Hu, Xinyuan Zhang, Linlin Qin, Menglu Chen, Wenzhuo Zhuang, Bingzong Li","doi":"10.1002/mc.70014","DOIUrl":"10.1002/mc.70014","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma characterized by high rates of relapse and limited responsiveness to standard chemotherapy. Selinxor, a selective inhibitor of XPO1, exhibited antitumor activity in various cancers. However, clinical trial results revealed that selinexor monotherapy exhibited unsatisfactory efficacy in DLBCL. Our study indicated that XPO1 expression was increased in DLBCL and was correlated with poor outcomes of DLBCL patients. Comprehensive proteomic and transcriptomics analysis showed that selinexor has significant impacts on various biological processes in DLBCL. Furthermore, we explored combination strategies involving selinexor to enhance DLBCL treatment. We examined the combined effects of selinexor with decitabine (DAC) and lenalidomide (LEN), and found that selinexor exhibited a synergistic effect with DAC against DLBCL. Further analysis revealed that DAC exerted a synergistic antitumor effect with selinexor by reversing the DNMT1 expression and DNA methylation alterations induced by selinexor. Overall, these findings provided valuable insights into the global impact of selinexor on DLBCL. The combination therapy of selinexor and DAC emerges as a highly promising strategy for effectively treating DLBCL, holding great potential for clinical application.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1609-1619"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626748","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":"Venetoclax Synergizes With Regorafenib for Colorectal Cancer by Targeting BCL-2.","authors":"Lijun Zhu, Weicheng Wang, Yuwen Dong, Xiao Han, Wei Zhang, Zhonghua Zhang, Wenjie Guo, Yanhong Gu","doi":"10.1002/mc.70017","DOIUrl":"10.1002/mc.70017","url":null,"abstract":"<p><p>Despite notable advancements in therapeutic modalities, many patients with colorectal cancer (CRC) exhibit inadequate response to regorafenib, largely due to the propensity for drug resistance. Deeper insights into the mechanism of CRC sensitivity to regorafenib therapy are urgently required. The antiapoptotic protein B-cell lymphoma 2 (BCL-2) is closely associated with a variety of malignancies. Therefore, this study investigated the role of BCL-2 in promoting regorafenib resistance in colorectal cancer. Venetoclax, a BCL-2 antagonist, potentiates the antitumor activity of regorafenib. The combination of regorafenib and Venetoclax inhibited the proliferation and promoted apoptosis of CRC cells and human umbilical vein endothelial cells in vitro by inhibiting tumor angiogenesis, promoting normalization of tumor blood vessels, and promoting immune cell infiltration and the release of immune cytotoxic factors. Although Venetoclax is primarily used clinically to treat hematological tumors, it has not yet been used to treat CRC. These findings provide new insights for the clinical treatment of CRC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1683-1696"},"PeriodicalIF":3.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708310","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}