Molecular Cancer Research最新文献_第3页

Mapping the FOXA1 Interactome in ER+ Breast Cancer Cells using Proximity Labeling Reveals Novel Interactions with the Orphan Nuclear Receptor NR2C2. 利用接近标记绘制ER+乳腺癌细胞中的FOXA1相互作用组揭示了与孤儿核受体NR2C2的新相互作用。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-28 DOI: 10.1158/1541-7786.MCR-25-0085

Rosemary N Plagens, Carla S Rodriquez Tirado, Shen Li, Natalia Maldonado-Vazquez, Ingrid M Montes-Rodriguez, Julie Dutil, Christine A Mills, Laura E Herring, Hector L Franco

{"title":"Mapping the FOXA1 Interactome in ER+ Breast Cancer Cells using Proximity Labeling Reveals Novel Interactions with the Orphan Nuclear Receptor NR2C2.","authors":"Rosemary N Plagens, Carla S Rodriquez Tirado, Shen Li, Natalia Maldonado-Vazquez, Ingrid M Montes-Rodriguez, Julie Dutil, Christine A Mills, Laura E Herring, Hector L Franco","doi":"10.1158/1541-7786.MCR-25-0085","DOIUrl":"10.1158/1541-7786.MCR-25-0085","url":null,"abstract":"FOXA1 is a pioneer transcription factor essential for chromatin accessibility and transcriptional regulation in hormone-driven cancers. In breast cancer, FOXA1 plays a central role in facilitating nuclear receptor binding, reprogramming enhancer landscapes, and promoting transcriptional changes associated with therapy resistance. While FOXA1's function has been primarily studied in the context of estrogen receptor-α (ER), its broader protein interaction network remains incompletely defined. Here, we systematically map FOXA1-interacting proteins in ER-positive breast cancer cells using proximity-dependent biotin labeling (miniTurbo) combined with quantitative LC-MS/MS proteomics. We engineered MCF-7 cell lines stably expressing miniTurbo-tagged FOXA1 at either the N-terminus or C-terminus to ensure comprehensive coverage of interaction interfaces. This approach recovered known FOXA1 partners, including AR, MLL3, YAP1, and GATA3, and identified 157 previously unreported FOXA1 interactors. Notably, 42 of these novel partners, including NR2C2, were significantly associated with poor relapse-free survival in ER+ breast cancer patients. To demonstrate the utility of this resource, we characterized the FOXA1-NR2C2 interaction in depth. Integrating ChIP-seq and RNA-seq, we show that FOXA1 and NR2C2 co-occupy a subset of genomic regions and drive co-regulated transcriptional programs involved in tumor progression. Our study reveals an expanded FOXA1 interactome and new insights into its functional network in breast cancer, providing candidate proteins for further exploration as biomarkers or therapeutic targets. Implications: These findings expand the FOXA1 interactome in breast cancer and uncover new candidate proteins with potential as biomarkers and therapeutic targets in hormone-driven tumors.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MACC1-AS1: An Emerging Star in The Field of Tumor Biology with Bright Futures in Medicine. MACC1-AS1：肿瘤生物学领域的一颗新星，医学前景光明。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-22 DOI: 10.1158/1541-7786.MCR-25-0170

Li Dong, Weidong Li, Wei Zhu, YaMin Sun

{"title":"MACC1-AS1: An Emerging Star in The Field of Tumor Biology with Bright Futures in Medicine.","authors":"Li Dong, Weidong Li, Wei Zhu, YaMin Sun","doi":"10.1158/1541-7786.MCR-25-0170","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0170","url":null,"abstract":"Long non-coding RNAs act as modulators, with significant influence on a wide array of biological functions. They form an extensive communication network between genes and contribute to the pathophysiology of various human diseases, especially cancer. A growing body of research has demonstrated that LncRNAs, acting either as promoters or inhibitors of oncogenesis, are intricately linked to the initiation and progression of cancer. MACC1-AS1 is a newly identified LncRNA that is abnormally expressed in various types of human tumors. Poor clinical characteristics, such as larger tumor size, advanced tumor stage, lymph node metastasis, and a lower overall survival rate, are linked to overexpression of MACC1-AS1. MACC1-AS1 exerts a complex regulatory function: it acts as a competitive RNA, interacts with multiple proteins, and influences diverse pathways, leading to tumor development. It is essential to note the decreased efficacy of conventional chemotherapy drugs, which diminishes the efficacy of cancer treatment. Ongoing research has been highlighting the multifaceted functions of MACC1-AS1, and thus, it is required to unravel its exact molecular mechanisms. In this overarching review, we explore the significance of MACC1-AS1 as a potential cancer treatment target and biomarker. This study can potentially play an important role in the advancement of the field and confirm its potential clinical applicability.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962317","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}

引用次数: 0

Tumor Cholesterol Synthesis, Statin Use, and Lethal Prostate Cancer. 肿瘤胆固醇合成，他汀类药物的使用和致死性前列腺癌。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-05 DOI: 10.1158/1541-7786.MCR-24-0864

Sinead Flanagan, Rosina T Lis, Ying Huang, Lina Jehane, Jane B Vaselkiv, Emma H Allott, Stephen P Finn, Tamara L Lotan, Michelangelo Fiorentino, Massimo Loda, Gwo-Shu Mary Lee, Goutam Chakraborty, Philip W Kantoff, Lorelei A Mucci, Konrad H Stopsack

{"title":"Tumor Cholesterol Synthesis, Statin Use, and Lethal Prostate Cancer.","authors":"Sinead Flanagan, Rosina T Lis, Ying Huang, Lina Jehane, Jane B Vaselkiv, Emma H Allott, Stephen P Finn, Tamara L Lotan, Michelangelo Fiorentino, Massimo Loda, Gwo-Shu Mary Lee, Goutam Chakraborty, Philip W Kantoff, Lorelei A Mucci, Konrad H Stopsack","doi":"10.1158/1541-7786.MCR-24-0864","DOIUrl":"10.1158/1541-7786.MCR-24-0864","url":null,"abstract":"Prostate tumor cells produce cholesterol de novo, and statin therapy targets the initial rate-limiting enzyme in this process, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). The extent to which the expression of HMGCR in prostate tumors could influence progression and predict the potential anti-neoplastic effects of statins remains unclear. In a prospective cohort study of 1098 men diagnosed with primary prostate cancer in 1982-2009 from the Health Professionals Follow-up Study and Physicians' Health Study, 16% of prostate tumors showed strong HMGCR staining intensity and 31% no staining. HMGCR expression was higher in tumors with PTEN loss but did not differ by statin use or long-term dietary cholesterol or saturated fat intake. Participants were followed for lethal events (distant metastases or prostate cancer-related death) over up to 32 years, and 96 lethal events occurred in those without metastases at diagnosis. Strong HMGCR expression was associated with higher rates of lethal prostate cancer (hazard ratio 2.2, 95% confidence interval 1.3-3.7), adjusting for age at diagnosis and Gleason score but without a linear dose response. In vitro in the LNCaP human prostate cancer cell line, atorvastatin impacted tumor cell viability in cells with experimentally lowered HMGCR expression. This study corroborates that high cholesterol synthesis in prostate tumor cells is associated with PTEN loss, aggressive tumor characteristics, and a greater risk of lethality. Implications: High expression of HMGCR, the first rate-limited enzyme of cholesterol synthesis, is a feature of prostate tumors that are more likely to progress to metastatic disease or death from prostate cancer.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeted Deletion of Cxcl1 in MSCs Regulates Osteogenesis and Suppresses Bone-Metastatic Prostate Cancer. MSCs中Cxcl1的靶向缺失促进骨生成并抑制骨转移性前列腺癌。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-04 DOI: 10.1158/1541-7786.MCR-24-0672

Catherine S Johnson, Diane Costanzo-Garvey, Julio C Valencia, Sanjana Rajgopal, Theodore Reed, Emma R Brannon, Jeremy S Frieling, Deanna D Mosley, Todd A Wyatt, Elijah F Edmondson, Kabhilan Mohan, Grinu Mathew, Leah M Cook

{"title":"Targeted Deletion of Cxcl1 in MSCs Regulates Osteogenesis and Suppresses Bone-Metastatic Prostate Cancer.","authors":"Catherine S Johnson, Diane Costanzo-Garvey, Julio C Valencia, Sanjana Rajgopal, Theodore Reed, Emma R Brannon, Jeremy S Frieling, Deanna D Mosley, Todd A Wyatt, Elijah F Edmondson, Kabhilan Mohan, Grinu Mathew, Leah M Cook","doi":"10.1158/1541-7786.MCR-24-0672","DOIUrl":"10.1158/1541-7786.MCR-24-0672","url":null,"abstract":"Bone metastasis continues to be the greatest challenge in treating patients with prostate cancer despite ongoing research. In bone, prostate cancer tumors hijack normal bone remodeling processes to drive cancer progression. However, it is unclear how these interactions drive bone-metastatic prostate cancer growth in the bone environment. To understand the mechanisms associated with bone-metastatic prostate cancer regulation of mesenchymal stem cells (MSC), we previously identified that bone-metastatic prostate cancer induces MSC expression of the pro-inflammatory chemokine CXCL8 and its mouse functional homologue Cxcl1. To date, there has been little to no information about the role of CXCL1/8 in MSC biology and its impact in the tumor-bone environment. Using genetic deletion of Cxcl1, we discovered a novel role for Cxcl1/8 in regulating MSC osteoblast differentiation, such that targeted deletion of Cxcl1 enhanced MSC osteoblastogenesis. Despite the osteogenic nature of prostate cancer, co-injection of Cxcl1 knockout (KO) MSCs with bone-metastatic prostate cancer in bone significantly suppressed tumor growth compared with co-injection with scrambled control (non-targeting) MSCs, even in the presence of three times more prostate cancer to MSCs. Furthermore, bulk RNA sequencing revealed immune response pathways, both in Cxcl1-KO MSCs and bone-metastatic prostate cancer tumors containing Cxcl1-KO MSCs. In support of this, Cxcl1-KO MSCs reduced immature neutrophils in the bone environment, while increasing monocytes. These findings demonstrate the importance of MSC-derived Cxcl1 in the bone microenvironment and highlight the importance of Cxcl1 in bone-metastatic prostate cancer progression.Implications: MSC-derived Cxcl1 regulates prostate cancer progression in bone.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"739-758"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12319404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

m6A-Modified SFTA1P Acts as a Tumor Suppressor in Non-Small Cell Lung Cancer by Regulating TGFBR2 and P-TEFb. m6A修饰的SFTA1P通过调节TGFBR2和P-TEFb在非小细胞肺癌中发挥抑瘤作用。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-04 DOI: 10.1158/1541-7786.MCR-24-0499

Tingting Xia, Menglei Chen, Meiyu Zhou, Weiping Wan, Yifan Shan, Weijia Xie, Na Wu, Chengying Li, Zhiquan Yuan, Tongjian Cai, Zubin Yu, Ying Xiang, Li Bai, Yafei Li

{"title":"m6A-Modified SFTA1P Acts as a Tumor Suppressor in Non-Small Cell Lung Cancer by Regulating TGFBR2 and P-TEFb.","authors":"Tingting Xia, Menglei Chen, Meiyu Zhou, Weiping Wan, Yifan Shan, Weijia Xie, Na Wu, Chengying Li, Zhiquan Yuan, Tongjian Cai, Zubin Yu, Ying Xiang, Li Bai, Yafei Li","doi":"10.1158/1541-7786.MCR-24-0499","DOIUrl":"10.1158/1541-7786.MCR-24-0499","url":null,"abstract":"SFTA1P is a pseudogene-derived long noncoding RNA and has become a master regulator in tumor carcinogenesis and progression processes. SFTA1P has been reported as a potential diagnostic and prognostic biomarker in non-small cell lung cancer (NSCLC). The downregulation of SFTA1P in tumor tissue has been associated with poor prognosis; however, the detailed molecular mechanism and biological functions still need to be investigated. We demonstrated that SFTA1P inhibited the growth and metastasis of NSCLC in vitro and in vivo. SFTA1P had dual functions in the cytoplasm and nucleus: In the cytoplasm, SFTA1P can serve as a \"sponge\" for miR-665 to increase the expression level of TGFBR2; in the nucleus, SFTA1P can bind the positive transcription elongation factor b and subsequently inhibit the transcriptase activity of RNA polymerase II. The regulation of TGFBR2 and positive transcription elongation factor b via SFTA1P depends on its subcellular localization, which was affected by the status of the N6-methyladenosine RNA modification of SFTA1P. Our research demonstrated that the candidate tumor-suppressor SFTA1P is extensively involved in NSCLC, which may offer novel insights into NSCLC oncogenesis.Implications: SFTA1P is downregulated in NSCLC and had dual functions in the cytoplasm and nucleus.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"710-723"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764503","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}

引用次数: 0

VAV2 Drives EGFR-Mediated Rac1 Responses in Prostate Cancer. 前列腺癌中VAV2驱动egfr介导的Rac1反应

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-04 DOI: 10.1158/1541-7786.MCR-24-0957

Martin J Baker, Suli Zhang, Daniel Zhang, Joshua Searle, Priti Lal, Cornelis P Vlaar, Surangani Dharmawardhane, Martín C Abba, Marcelo G Kazanietz, Mariana Cooke

{"title":"VAV2 Drives EGFR-Mediated Rac1 Responses in Prostate Cancer.","authors":"Martin J Baker, Suli Zhang, Daniel Zhang, Joshua Searle, Priti Lal, Cornelis P Vlaar, Surangani Dharmawardhane, Martín C Abba, Marcelo G Kazanietz, Mariana Cooke","doi":"10.1158/1541-7786.MCR-24-0957","DOIUrl":"10.1158/1541-7786.MCR-24-0957","url":null,"abstract":"The small G-protein Rac1 is a central player in cancer progression and metastatic dissemination. Rac1 has been established as a bona fide effector of receptor tyrosine kinases, acting as a signaling node for motility, invasiveness, mitogenesis, and gene expression. Previous studies demonstrated that Rac1 is hyperactivated in aggressive cellular models of prostate cancer. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of Rac1 results in impaired proliferation and migration of prostate cancer cells. Rac1-null cells display profound alterations in transcriptional programs, particularly those associated with cell adhesion and extracellular matrix regulation. Combined expression profiling and unbiased RNAi screening of Rac1 guanine nucleotide exchange factors identified VAV2 as the foremost mediator EGF-induced GTP loading onto Rac1 in prostate cancer cells. Depletion of VAV2 from prostate cancer cells significantly reduced their proliferative and migratory capacities without affecting the expression of Rac1-regulated genes, suggesting that VAV2 controls a discrete subset of Rac1-dependent cellular responses. IHC assessment in human prostate biopsies showed significant VAV2 overexpression in tumor areas. Bioinformatic analysis revealed a strong correlation between VAV2 expression and poor clinical prognosis. In addition to uncovering a prominent role for VAV2-Rac1 as an effector pathway mediating EGFR-driven proliferative and migratory responses in prostate cancer cells, our findings underscore the potential prognostic value of VAV2 in human prostate cancer progression.Implications: This study highlights the central role of VAV2 in prostate cancer cell proliferation and migration, as well as its potential prognostic value in disease progression.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"684-698"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Impact of Cancer Therapy on the Cells and Extracellular Vesicles of the Tumor Immune Microenvironment. 肿瘤治疗对肿瘤免疫微环境细胞和细胞外囊泡的影响。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-04 DOI: 10.1158/1541-7786.MCR-25-0101

Claire Bruno, Andrew Whitcomb, Brooke Pincock, Israel Davila Aleman, Jacob H Neves, Matthew Shaw, Amber Gonda

{"title":"The Impact of Cancer Therapy on the Cells and Extracellular Vesicles of the Tumor Immune Microenvironment.","authors":"Claire Bruno, Andrew Whitcomb, Brooke Pincock, Israel Davila Aleman, Jacob H Neves, Matthew Shaw, Amber Gonda","doi":"10.1158/1541-7786.MCR-25-0101","DOIUrl":"10.1158/1541-7786.MCR-25-0101","url":null,"abstract":"Cancer remains one of the leading causes of morbidity and mortality worldwide, necessitating the development of diverse treatment options to improve patient outcomes. The tumor microenvironment (TME) plays a critical role in determining the efficacy of these different therapies, yet the reciprocal impact of treatment on the TME, particularly the tumor immune microenvironment (TIME), remains incompletely understood. This review investigates the different effects of cancer therapies-chemotherapy, targeted therapy, immunotherapy, and radiotherapy-on immune cells within the TIME and associated extracellular vesicles (EV). The broader impact on the TME belies a complex and nuanced tumor response. These treatments have been shown to have an impact on the function of various immune cells, influencing their activity to either promote or block tumor growth. Importantly, this review also considers how these therapies play an indirect role in modulating the TIME by influencing the release and contents of EVs, highlighting the significant role that EVs play in intercellular communication within the TIME. By analyzing recent findings, this review aims to provide a comprehensive understanding of how different cancer therapies reshape the TIME. Understanding these dynamic relationships can help pave the way for optimizing existing treatments, developing new therapies, and enhancing patient outcomes.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"673-683"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234612","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}

引用次数: 0

Spatial Analysis of Hereditary Diffuse Gastric Cancer Reveals Indolent Phenotype of Signet Ring Cell Precursors. 遗传性弥漫性胃癌的空间分析揭示了印戒细胞前体的惰性表型。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-04 DOI: 10.1158/1541-7786.MCR-24-1039

Amber F Gallanis, Lauren A Gamble, Cihan Oguz, Sarah G Samaranayake, Noemi Kedei, Maria O Hernandez, Madeline Wong, Desiree Tillo, Benjamin L Green, Paul McClelland, Cassidy Bowden, Irene Gullo, Mark Raffeld, Liqiang Xi, Michael Kelly, Markku Miettinen, Martha Quezado, Sun A Kim, Andrew M Blakely, Justin Lack, Theo Heller, Jonathan M Hernandez, Jeremy L Davis

{"title":"Spatial Analysis of Hereditary Diffuse Gastric Cancer Reveals Indolent Phenotype of Signet Ring Cell Precursors.","authors":"Amber F Gallanis, Lauren A Gamble, Cihan Oguz, Sarah G Samaranayake, Noemi Kedei, Maria O Hernandez, Madeline Wong, Desiree Tillo, Benjamin L Green, Paul McClelland, Cassidy Bowden, Irene Gullo, Mark Raffeld, Liqiang Xi, Michael Kelly, Markku Miettinen, Martha Quezado, Sun A Kim, Andrew M Blakely, Justin Lack, Theo Heller, Jonathan M Hernandez, Jeremy L Davis","doi":"10.1158/1541-7786.MCR-24-1039","DOIUrl":"10.1158/1541-7786.MCR-24-1039","url":null,"abstract":"Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multiomic analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of extracellular matrix remodeling in SRC lesions compared with unaffected adjacent gastric epithelium. Single-cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, and KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin reexpression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared with SRC lesions.Implications: The marked differences in the genomic and transcriptomic profiles of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"699-709"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

METTL3 Promotes Gastric Cancer Progression via Modulation of FNTA-Mediated KRAS/ERK Signaling Activation. METTL3通过调控fnta介导的KRAS/ERK信号激活促进胃癌进展。

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-04 DOI: 10.1158/1541-7786.MCR-24-1168

Fangqi Hu, Song Zhang, Jie Chai

{"title":"METTL3 Promotes Gastric Cancer Progression via Modulation of FNTA-Mediated KRAS/ERK Signaling Activation.","authors":"Fangqi Hu, Song Zhang, Jie Chai","doi":"10.1158/1541-7786.MCR-24-1168","DOIUrl":"10.1158/1541-7786.MCR-24-1168","url":null,"abstract":"As a vital form of posttranscriptional modification, RNA N6-methyladenosine (m6A) methylation dysregulation is usually associated with the pathogenesis of a range of diseases, including cancer, but the function and underlying mechanisms of m6A in regulating gastric cancer initiation and progression are still poorly understood. In this study, we have found that methyltransferase-like 3 (METTL3) and the level of RNA m6A modification were significantly upregulated in gastric cancerous tissues relative to their normal counterparts. In addition, higher METTL3 expression always predicted poorer outcomes for patients with gastric cancer. Methylated RNA sequencing revealed that METTL3 deposited m6A modification on farnesyltransferase, subunit alpha (FNTA) mRNA and accelerated its translation relying on YTH N6-methyladenosine RNA-binding protein 1 recognition. When METTL3 or FNTA expression was silenced in gastric cancer cells, the FNTA-mediated KRAS plasma membrane distribution was disrupted, resulting in downstream MEK/ERK signaling inactivation, which finally contributed to gastric cancer suppression in vitro and in vivo. In summary, our studies revealed a cross-talk between METTL3-mediated RNA methylation and FNTA-mediated protein modification, which synergized to drive gastric cancer progression through orchestrating KRAS/ERK signaling activity.Implications: Targeting the METTL3/FNTA pathway will provide an alternative to overcome the resistance of gastric cancer to canonical KRAS inhibitors.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"724-738"},"PeriodicalIF":4.7,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002697","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}

引用次数: 0

The LINC00519/hsa-miR-22-3p/MECOM Axis Accelerates Intrahepatic Cholangiocarcinoma Progression Through PI3K/AKT Signaling. LINC00519/hsa-miR-22-3p/MECOM轴通过PI3K/AKT信号通路加速肝内胆管癌进展

IF 4.7 2区医学

Molecular Cancer Research Pub Date : 2025-08-01 DOI: 10.1158/1541-7786.MCR-25-0207

Zhuxin Gu, Yanjun Sun, Fajing Chen, Weiwei Gu, Xiaohua Lu, Suming Zhao, Qinan Geng, Yang Yang

{"title":"The LINC00519/hsa-miR-22-3p/MECOM Axis Accelerates Intrahepatic Cholangiocarcinoma Progression Through PI3K/AKT Signaling.","authors":"Zhuxin Gu, Yanjun Sun, Fajing Chen, Weiwei Gu, Xiaohua Lu, Suming Zhao, Qinan Geng, Yang Yang","doi":"10.1158/1541-7786.MCR-25-0207","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-25-0207","url":null,"abstract":"Intrahepatic cholangiocarcinoma (ICC) is the second most common liver cancer. LINC00519 plays prominent roles in the progression of numerous cancers. To explore the molecular mechanism of LINC00519 in ICC, LINC00519, hsa-miR-22-3p, and MECOM expressions in ICC were assessed with ENCORI database and quantitative real-time PCR. Biological functions of LINC00519 in ICC were examined using clone formation experiment, Transwell analysis, flow cytometry, and Western blot. Meanwhile, the LINC00519 mechanism in ICC was determined by dual-luciferase reporter assay. Results showed that LINC00519 and MECOM were highly expressed in ICC, but hsa-miR-22-3p was decreased. Functionally, silencing LINC00519 weakened ICC cell proliferation, migration and induced cell apoptosis. Also, LINC00519 knockdown repressed PI3K/AKT pathway. Mechanistically, LINC00519 acted as a competitive endogenous RNA to target MECOM by sponging hsa-miR-22-3p. Meanwhile, rescue assays further proved that low LINC00519 expression restrained ICC cell proliferation and migration, and accelerated apoptosis through PI3K/AKT pathway by miR-22-3p/MECOM. In conclusion, this research revealed a novel LINC00519/hsa-miR-22-3p/MECOM regulatory axis and PI3K/AKT pathway that modulated ICC progression. Implications: This study deepens the understanding of the non-coding RNA regulatory network in ICC and provides potential targets for the diagnosis and targeted therapy of ICC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760600","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}

引用次数: 0