Molecular Cancer Research最新文献_第2页

METTL14-Mediated Bim mRNA m6A Modification Augments Osimertinib Sensitivity in EGFR-Mutant NSCLC Cells. METTL14 介导的 Bim mRNA m6A 修饰增强了表皮生长因子受体突变 NSCLC 细胞对奥希替尼的敏感性。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-11-01 DOI: 10.1158/1541-7786.MCR-23-1018

Siwen Fan, Xinwu Lv, Chuantao Zhang, Bingbing Zeng, Yanqing Liang, Danyang Chen, Zumin Xu, Pan Li, Shanshan Wu, Hao Liu, Kai Luo, Zongcai Liu, Yanmei Yi

{"title":"METTL14-Mediated Bim mRNA m6A Modification Augments Osimertinib Sensitivity in EGFR-Mutant NSCLC Cells.","authors":"Siwen Fan, Xinwu Lv, Chuantao Zhang, Bingbing Zeng, Yanqing Liang, Danyang Chen, Zumin Xu, Pan Li, Shanshan Wu, Hao Liu, Kai Luo, Zongcai Liu, Yanmei Yi","doi":"10.1158/1541-7786.MCR-23-1018","DOIUrl":"10.1158/1541-7786.MCR-23-1018","url":null,"abstract":"Resistance to osimertinib represents a significant challenge for the successful treatment of non-small cell lung cancer (NSCLC) harboring activating mutations in EGFR. N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates osimertinib resistance of NSCLC remains unknown. In this study, we demonstrated that developing osimertinib-resistant phenotypes depends on m6A reduction resulting from downexpression of m6A methyltransferase METTL14 in EGFR-mutant NSCLCs. Both in vitro and in vivo assays showed that specific knockdown of METTL14 was sufficient to confer osimertinib resistance and that elevated expression of METTL14 rescued the efficacy of osimertinib in the resistant NSCLC cells. Mechanistically, METTL14 promoted m6A methylation of pro-apoptotic Bim mRNA and increased Bim mRNA stability and expression, resulting in activating the Bim-dependent pro-apoptotic signaling and thereby promoting osimertinib-induced cell apoptosis. Analysis of clinical samples revealed that decreased expression of METTL14 was observed in osimertinib-resistant NSCLC tissues and significantly associated with a poor prognosis. In conclusion, our study reveals a novel regulatory mechanism by which METTL14-mediated m6A methylation of Bim mRNA inhibited osimertinib resistance of NSCLC cells. It offers more evidences for the involvement of m6A modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors. Implications: This study offers more evidences for the involvement of METTL14-mediated N6-methyladenosine modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1051-1063"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492786","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

Retraction: KRAS Activation in Gastric Adenocarcinoma Stimulates Epithelial-to-Mesenchymal Transition to Cancer Stem-Like Cells and Promotes Metastasis. 撤回：胃腺癌中的 KRAS 激活会刺激上皮细胞向癌干样细胞的间质转化并促进转移。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-11-01 DOI: 10.1158/1541-7786.MCR-24-0858

Changhwan Yoon, Jacob Till, Soo-Jeong Cho, Kevin K Chang, Jian-Xian Lin, Chang-Ming Huang, Sandra Ryeom, Sam S Yoon

引用次数: 0

NAP1L1 Promotes Endometrial Cancer Progression via EP300-Mediated DDX5 Promoter Acetylation. NAP1L1 通过 EP300 介导的 DDX5 启动子乙酰化促进子宫内膜癌进展

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-11-01 DOI: 10.1158/1541-7786.MCR-23-0871

Xiangfei Zhu, Yishan Li, Zhiying Shao, Xiaoyuan Lu, Youguo Chen

{"title":"NAP1L1 Promotes Endometrial Cancer Progression via EP300-Mediated DDX5 Promoter Acetylation.","authors":"Xiangfei Zhu, Yishan Li, Zhiying Shao, Xiaoyuan Lu, Youguo Chen","doi":"10.1158/1541-7786.MCR-23-0871","DOIUrl":"10.1158/1541-7786.MCR-23-0871","url":null,"abstract":"Endometrial cancer is one of the predominant tumors of the female reproductive system. In this current study, we investigated the functions and related mechanisms of nucleosome assembly protein 1 like 1 (NAP1L1)/ DEAD-box helicase 5 (DDX5) in endometrial cancer. This retrospective study analyzed the medical records of patients with endometrial cancer, collected tissue samples for NAP1L1 and DDX5 staining, and conducted survival analysis using the Kaplan-Meier method. To evaluate the impact of NAP1L1 and/or DDX5 on cellular processes in endometrial cancer cells, several techniques were employed. These included Cell Counting Kit-8 assay, wound healing assay, Transwell assay, as well as overexpression or knockdown of target gene expression. Additionally, chromatin immunoprecipitation, dual luciferase reporter gene, and coimmunoprecipitation (Co-IP) assay were utilized to confirm the interaction between NAP1L1, E1A-binding protein p300 (EP300), and DDX5. Furthermore, qRT-PCR, Western blot, and Co-IP assay were performed to analyze the modulation of NAP1L1/DDX5 in Wnt/β-catenin. NAP1L1 and DDX5 expression were upregulated in endometrial cancer tissues, and correlated with poor prognosis. NAP1L1/DDX5 promoted endometrial cancer cell proliferation, migration, and invasion. NAP1L1 promotes acetylation and transcription by recruiting EP300 to the DDX5 promoter. DDX5 could activate Wnt/β-catenin signal by binding to β-catenin. In animal models, knockdown of NAP1L1 inhibits endometrial cancer tumor growth and lung metastasis. To sum up, our study demonstrated that NAP1L1 promoted the malignant phenotypes of endometrial cancer cells via recruiting EP300 to promote DDX5 acetylation, thus activating the Wnt/β-catenin signaling pathway. Implications: Our research findings indicate that targeting the NAP1L1/EP300/DX5 axis might be a new potential treatment option for endometrial cancer.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1011-1021"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492801","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

lncRNA-WAL Promotes Triple-Negative Breast Cancer Aggression by Inducing β-Catenin Nuclear Translocation. lncRNA-WAL通过诱导β-catenin核易位促进三阴性乳腺癌的侵袭。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-11-01 DOI: 10.1158/1541-7786.MCR-23-0334

Hongyan Huang, Haiyun Jin, Rong Lei, Zhanghai He, Shishi He, Jiewen Chen, Phei E Saw, Zhu Qiu, Guosheng Ren, Yan Nie

{"title":"lncRNA-WAL Promotes Triple-Negative Breast Cancer Aggression by Inducing β-Catenin Nuclear Translocation.","authors":"Hongyan Huang, Haiyun Jin, Rong Lei, Zhanghai He, Shishi He, Jiewen Chen, Phei E Saw, Zhu Qiu, Guosheng Ren, Yan Nie","doi":"10.1158/1541-7786.MCR-23-0334","DOIUrl":"10.1158/1541-7786.MCR-23-0334","url":null,"abstract":"Because of its insensitivity to existing radiotherapy, namely, chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/β-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated Wnt/β-catenin pathway of TNBC tissues, lnc-WAL (Wnt/β-catenin-associated lncRNA; WAL) was selected as the top upregulated lncRNA in Wnt/β-catenin pathway activation compared with the inactivation group. RNA immunoprecipitation sequencing was used to compare the β-catenin and IgG groups, in which lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted epithelial-mesenchymal transition, the proliferation, migration, and invasion of breast cancer stem cells and TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via AXIN-mediated phosphorylation at serine 45. Subsequently, β-catenin accumulated in the nucleus and activated the target genes. Importantly, Wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/AXIN/β-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/β-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for patients with TNBC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1036-1050"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469682","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

hnRNPAB Promotes Pancreatic Ductal Adenocarcinoma Extravasation and Liver Metastasis by Stabilizing MYC mRNA. HnRNPAB 通过稳定 MYC mRNA 促进胰腺导管腺癌的外渗和肝转移。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-11-01 DOI: 10.1158/1541-7786.MCR-24-0110

Ke Lei, Mingyue Sun, Xianghan Chen, Jia Wang, Xiaolan Liu, Ying Ning, Shuai Ping, Ruining Gong, Yu Zhang, Gong Qing, Chenyang Zhao, He Ren

{"title":"hnRNPAB Promotes Pancreatic Ductal Adenocarcinoma Extravasation and Liver Metastasis by Stabilizing MYC mRNA.","authors":"Ke Lei, Mingyue Sun, Xianghan Chen, Jia Wang, Xiaolan Liu, Ying Ning, Shuai Ping, Ruining Gong, Yu Zhang, Gong Qing, Chenyang Zhao, He Ren","doi":"10.1158/1541-7786.MCR-24-0110","DOIUrl":"10.1158/1541-7786.MCR-24-0110","url":null,"abstract":"Heterogeneous nuclear ribonucleoprotein AB (hnRNPAB) is considered a cancer-promoting heterogeneous nuclear ribonucleoprotein in many cancers, but its function in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. hnRNPAB was highly expressed in PDAC tissues compared with normal pancreatic tissues, and high expression of hnRNPAB was associated with poor overall survival and recurrence-free survival in patients with PDAC. hnRNPAB promotes migration and invasion of PDAC cells in vitro. In xenograft tumor mouse models, hnRNPAB deprivation significantly attenuated liver metastasis. hnRNPAB mRNA and protein levels are positively associated with MYC in PDAC cells. Mechanistically, hnRNPAB bound to MYC mRNA and prolonged its half-life. hnRNPAB induced PDAC cells to secrete CXCL8 via MYC, which promoted neutrophil recruitment and facilitated tumor cells entrancing into the hepatic parenchyma. These findings point to a novel regulatory mechanism via which hnRNPAB promotes PDAC metastasis. Implications: hnRNPAB participates in the posttranscriptional regulation of the oncogene MYC by binding and stabilizing MYC mRNA, thereby promoting liver metastasis in PDAC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1022-1035"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534886","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

Genome Instability Precedes Viral Integration in Human Papilloma Virus Transformed Tonsillar Keratinocytes. 人类乳头状瘤病毒转化的扁桃体角质细胞中病毒整合前的基因组不稳定性

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-10-30 DOI: 10.1158/1541-7786.MCR-24-0604

Kimberly Chan, Christopher Tseng, Emily Milarachi, David Goldrich, Lisa Schneper, Kathryn Sheldon, Cesar Aliaga, Samina Alam, Sreejata Chatterjee, Karam El-Bayoumy, Craig Meyers, David Goldenberg, James R Broach

{"title":"Genome Instability Precedes Viral Integration in Human Papilloma Virus Transformed Tonsillar Keratinocytes.","authors":"Kimberly Chan, Christopher Tseng, Emily Milarachi, David Goldrich, Lisa Schneper, Kathryn Sheldon, Cesar Aliaga, Samina Alam, Sreejata Chatterjee, Karam El-Bayoumy, Craig Meyers, David Goldenberg, James R Broach","doi":"10.1158/1541-7786.MCR-24-0604","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0604","url":null,"abstract":"Approximately 70% of oropharyngeal squamous carcinomas (OPSCC) are associated with human papillomavirus (HPV). While patients with HPV-positive tumors generally have better outcomes than those with HPV-negative tumors, a subset of HPV-positive patients do have poor outcomes. Our previous work suggested that tumors with integrated virus exhibit significantly greater genome wide genomic instability than those with only episomal viral genomes and patients with HPV+ OPSCC with episomal viral genomes had better outcomes. To explore the causal relation between viral integration and genomic instability, we have examined the time course of viral integration and genetic instability in tonsillar keratinocytes transformed with HPV16. HPV-infected human tonsil keratinocyte cell lines were continuously passaged and every fifth passage some cells were retained for genomic analysis. Whole genome sequencing and optical genomic mapping confirmed that virus integrated in five of six cell lines while remaining episomal in the sixth. In all lines genome instability occurred during early passages, but essentially ceased following viral integration but continued to occur later passages in the episomal line. To test tumorigenicity of the cell lines, cells were injected subcutaneously into the flanks of nude mice. A cell line with the integrated virus induced tumors following injection in the nude mouse while that with the episomal virus did not. Implications: Genomic instability in HPV OPSCC tumors is not the result of viral integration but likely promotes integration. Moreover, transformants with episomal virus appear to be less tumorigenic than those with integrated virus.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546520","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

Intra- and Extrahepatic Cholangiocarcinomas Display Differing Sensitivities to NK Cell Lysis and Modulate NK Cell Function Through Shared and Distinct Pathways. 肝内和肝外胆管癌对 NK 细胞溶解的敏感性不同，并通过共同和不同的途径调节 NK 细胞功能。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-10-22 DOI: 10.1158/1541-7786.MCR-24-0299

Ian C Henrich, Ngan Nguyen

{"title":"Intra- and Extrahepatic Cholangiocarcinomas Display Differing Sensitivities to NK Cell Lysis and Modulate NK Cell Function Through Shared and Distinct Pathways.","authors":"Ian C Henrich, Ngan Nguyen","doi":"10.1158/1541-7786.MCR-24-0299","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0299","url":null,"abstract":"Cholangiocarcinoma (CCA) is a rare cancer that arises from the bile duct and is broadly classified by the location of the tumor as either intrahepatic (iCCA) or extrahepatic (eCCA). Immunotherapy has revolutionized cancer treatment, yet its utility in CCA has been limited as the tumor microenvironment (TME) in CCA is poorly understood compared to other common cancers. Utilizing previously published transcriptome data, our re-analysis has revealed that CCA has one of the highest relative levels of natural killer (NK) cells, a potent cytotoxic immune cell, compared to other cancers. However, despite iCCA and eCCA having comparable relative levels of NK infiltration, NK cell infiltration only correlated with survival in eCCA patients. Our subsequent investigation revealed that while iCCA and eCCA profoundly altered NK activity, eCCA had a significantly reduced impact on NK functionality. Whereas iCCA was resistant to long-term NK co-culture, eCCA was markedly more sensitive. Moreover, while both iCCA and eCCA dysregulated key NK activating receptors, eCCA co-culture did not impact NKp30 nor NKp44 expression. Furthermore, tumor transcriptome analysis of NKHigh CCA samples revealed modulation of multiple immune and non-immune cell types within the TME. Implications: These studies are the first to investigate how iCCA and eCCA impact NK cell functionality through shared and distinct mechanisms and how elevated NK cell infiltration could shape the CCA TME in a subtype-dependent manner.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470750","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

PRMT5 maintains tumor stem cells to promote pediatric high-grade glioma tumorigenesis. PRMT5 可维持肿瘤干细胞，促进小儿高级别胶质瘤的发生。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-10-18 DOI: 10.1158/1541-7786.MCR-24-0233

John DeSisto, Ilango Balakrishnan, Aaron J Knox, Gabrielle Link, Sujatha Venkataraman, Rajeev Vibhakar, Adam L Green

{"title":"PRMT5 maintains tumor stem cells to promote pediatric high-grade glioma tumorigenesis.","authors":"John DeSisto, Ilango Balakrishnan, Aaron J Knox, Gabrielle Link, Sujatha Venkataraman, Rajeev Vibhakar, Adam L Green","doi":"10.1158/1541-7786.MCR-24-0233","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0233","url":null,"abstract":"Pediatric high-grade gliomas (PHGG) are aggressive, undifferentiated CNS tumors with poor outcomes, for which no standard-of-care drug therapy currently exists. Through a knockdown screen for epigenetic regulators, we identified PRMT5 as essential for PHGG cell growth. We hypothesized that, similar to its effect in normal cells, PRMT5 promotes self-renewal of stem-like PHGG tumor initiating cells (TICs) essential for tumor growth. We conducted in vitro analyses, including limiting dilution studies of self-renewal, to determine the phenotypic effects of PRMT5 KD. We performed ChIP-Seq to identify PRMT5-mediated epigenetic changes and performed gene set enrichment analysis to identify pathways that PRMT5 regulates. Using an orthotopic xenograft model of PHGG, we tracked survival and histological characteristics resulting from PRMT5 KD or administration of a PRMT5 inhibitor ± radiation therapy (RT). In vitro, PRMT5 KD slowed cell cycle progression, tumor growth and self-renewal, and altered chromatin occupancy at genes associated with differentiation, tumor formation and growth. In vivo, PRMT5 KD increased survival and reduced tumor aggressiveness; however, pharmacological inhibition of PRMT5 with or without RT did not improve survival. PRMT5 KD epigenetically reduced TIC self-renewal, leading to increased survival in preclinical models. Pharmacological inhibition of PRMT5 enzymatic activity may have failed in vivo due to insufficient reduction of PRMT5 activity by chemical inhibition, or this failure may suggest that non-enzymatic activities of PRMT5 are more relevant. Implications: PRMT5 maintains and promotes the growth of stemlike cells that initiate and drive tumorigenesis in pediatric high grade glioma.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470763","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

N-linked fucosylated glycans are biomarkers for prostate cancer with a neuroendocrine and metastatic phenotype. N-连接的岩藻糖基化聚糖是具有神经内分泌和转移表型的前列腺癌的生物标记物。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-10-17 DOI: 10.1158/1541-7786.MCR-24-0660

Joseph E Ippolito, Jordan P Hartig, Kaitlyn Bejar, Hani Nakhoul, Jennifer K Sehn, Cody Weimholt, Grace Grimsley, Elena Nunez, Nikolaos A Trikalinos, Deyali Chatterjee, Eric H Kim, Anand S Mehta, Peggi M Angel, Dean A Troyer, Robin J Leach, Eva Corey, Jennifer D Wu, Richard R Drake

{"title":"N-linked fucosylated glycans are biomarkers for prostate cancer with a neuroendocrine and metastatic phenotype.","authors":"Joseph E Ippolito, Jordan P Hartig, Kaitlyn Bejar, Hani Nakhoul, Jennifer K Sehn, Cody Weimholt, Grace Grimsley, Elena Nunez, Nikolaos A Trikalinos, Deyali Chatterjee, Eric H Kim, Anand S Mehta, Peggi M Angel, Dean A Troyer, Robin J Leach, Eva Corey, Jennifer D Wu, Richard R Drake","doi":"10.1158/1541-7786.MCR-24-0660","DOIUrl":"10.1158/1541-7786.MCR-24-0660","url":null,"abstract":"Prostate cancer (PCa) is a heterogeneous disease with a spectrum of pathology and outcomes ranging from indolent to lethal. Although there have been recent advancements in prognostic tissue biomarkers, limitations still exist. We leveraged Matrix Assisted Laser Desorption Ionization (MALDI) imaging of formalin-fixed, paraffin embedded (FFPE) prostate cancer specimens to determine if N-linked glycans expressed in the extracellular matrix of lethal neuroendocrine prostate cancer were also expressed in conventional prostate adenocarcinomas that were associated with poor outcomes. We found that N-glycan fucosylation was abundant in neuroendocrine prostate cancer as well as adenocarcinomas at time of prostatectomy that eventually developed recurrent metastatic disease. Analysis of patient derived xenografts revealed that this fucosylation signature was enriched differently across metastatic disease organ sites, with the highest abundance in liver metastases. These data suggest that N-linked fucosylated glycans could be an early tissue biomarker for poor PCa outcomes. Implications: These studies identify that hyper-fucosylated N-linked glycans are enriched in neuroendocrine prostate cancer and conventional prostate adenocarcinomas that progress to metastatic disease, thus advancing biomarker discovery and providing insights into mechanisms underlying metastatic disease.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470762","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 distinct roles of NEIL1 and XPA in limiting aflatoxin B₁-induced mutagenesis in mice. NEIL1和XPA在限制黄曲霉毒素B₁诱发小鼠突变中的不同作用。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-10-10 DOI: 10.1158/1541-7786.MCR-24-0577

Michael M Luzadder, Irina G Minko, Vladimir L Vartanian, Marten Davenport, Lev M Fedorov, Amanda K McCullough, R Stephen Lloyd

{"title":"The distinct roles of NEIL1 and XPA in limiting aflatoxin B₁-induced mutagenesis in mice.","authors":"Michael M Luzadder, Irina G Minko, Vladimir L Vartanian, Marten Davenport, Lev M Fedorov, Amanda K McCullough, R Stephen Lloyd","doi":"10.1158/1541-7786.MCR-24-0577","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0577","url":null,"abstract":"Dietary exposure to aflatoxin B₁ (AFB₁) is a risk factor for the development of hepatocellular carcinomas (HCCs). Following metabolic activation, AFB₁ reacts with guanines to form covalent DNA adducts, which induce high-frequency G > T transversions. The molecular signature associated with these mutational events aligns with the single base substitution signature 24 (SBS24) in the Catalog of Somatic Mutations in Cancer (COSMIC) database. Deficiencies in either base excision repair (BER) due to the absence of Nei-like DNA glycosylase 1 (NEIL1) or nucleotide excision repair (NER) due to the absence of xeroderma complementation group A protein (XPA) contribute to HCCs in murine models. In the current study, ultra-low error duplex sequencing was used to characterize mutational profiles in liver DNAs of NEIL1-deficient, XPA-deficient, and DNA repair-proficient mice following neonatal injection of 1 mg/kg AFB₁. Analyses of AFB₁-induced mutations showed high cosine similarity to SBS24, regardless of repair proficiency status. The absence of NEIL1 resulted in an approximately 30% increase in the frequency of mutations, with distribution suggesting preferential NEIL1-dependent repair of AFB₁ lesions in open chromatin regions. A trend of increased mutagenesis was also observed in the absence of XPA. Consistent with the role of XPA in transcription-coupled repair, mutational profiles in XPA-deficient mice showed disruption of the transcriptional bias in mutations associated with SBS24. Implications: Our findings define the roles of DNA repair pathways in AFB₁-induced mutagenesis and carcinogenesis in murine models, with these findings having implications in human health for those with BER and NER deficiencies.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470764","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