Molecular Cancer Research最新文献_第5页

KSR2 promotes self-renewal and clonogenicity of small-cell lung carcinoma. KSR2促进小细胞肺癌的自我更新和克隆原性。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-10 DOI: 10.1158/1541-7786.MCR-24-0546

Dianna H Huisman, Deepan Chatterjee, Robert A Svoboda, Heidi M Vieira, Abbie S Ireland, Sydney Skupa, James W Askew, Danielle E Frodyma, Luc Girard, Kurt W Fisher, Michael S Kareta, John D Minna, Trudy G Oliver, Robert E Lewis

{"title":"KSR2 promotes self-renewal and clonogenicity of small-cell lung carcinoma.","authors":"Dianna H Huisman, Deepan Chatterjee, Robert A Svoboda, Heidi M Vieira, Abbie S Ireland, Sydney Skupa, James W Askew, Danielle E Frodyma, Luc Girard, Kurt W Fisher, Michael S Kareta, John D Minna, Trudy G Oliver, Robert E Lewis","doi":"10.1158/1541-7786.MCR-24-0546","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0546","url":null,"abstract":"Small-cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells (PNECs) was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony forming ability of tumor propagating cells (TPCs) in vitro and their tumor initiating capacity in vivo. The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor propagating cell function, and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of ASCL1-subtype SCLC tumors, and a potential subtype-specific therapeutic target. Implications: Manipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597417","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

ANGEL2 modulates wildtype TP53 translation and doxorubicin chemosensitivity in colon cancer. ANGEL2 可调节结肠癌中野生型 TP53 的翻译和多柔比星的化学敏感性。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-07 DOI: 10.1158/1541-7786.MCR-24-0702

Christopher August Lucchesi, Saisamkalpa Mantrala, Darren Tran, Neelu Batra, Avani Durve, Conner Suen, Jin Zhang, Paramita Ghosh, Xinbin Chen

{"title":"ANGEL2 modulates wildtype TP53 translation and doxorubicin chemosensitivity in colon cancer.","authors":"Christopher August Lucchesi, Saisamkalpa Mantrala, Darren Tran, Neelu Batra, Avani Durve, Conner Suen, Jin Zhang, Paramita Ghosh, Xinbin Chen","doi":"10.1158/1541-7786.MCR-24-0702","DOIUrl":"10.1158/1541-7786.MCR-24-0702","url":null,"abstract":"Multiple lines of correlative evidence support a role for ANGEL2, a novel cancer-relevant RNA-binding protein, in the modulation of chemoresistance and cancer patient survival. However, to date, no study has determined a mechanism by which ANGEL2 modulates cancer progression, nor its role in chemoresistance. Herein, we demonstrate that loss of ANGEL2 leads to a substantial decrease of the key tumor suppressor protein TP53. We show that ANGEL2 directly interacts with EIF4E, the rate limiting protein in cap-dependent translation. This interaction abrogates the ability for the TP53 translation repressor RBM38 to interact with EIF4E thereby enhancing TP53 translation. Loss of ANGEL2 in cancer cell lines resulted in increased 2D and 3D spheroid cell growth, and resistance to doxorubicin and etoposide. With therapeutic potential, treatment with Pep7, a seven amino-acid peptide derived from ANGEL2, rescued wildtype TP53 expression and sensitized cancer cells to doxorubicin. Together, we conclude that ANGEL2 modulates the EIF4E-RBM38 complex to enhance wildtype TP53 translation, and further, the Pep7 peptide may be explored as a therapeutic strategy for cancers which harbor wildtype TP53 expression. Implications: Loss of ANGEL2 contributes to decreased wildtype TP53 translation promoting doxorubicin resistance which can be rescued via an ANGEL2-derived peptide.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573421","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

Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine Resistant Multiple Myeloma. 核糖体分析揭示Omacetaxine耐药多发性骨髓瘤通过mTOR激活的翻译重编程。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-06 DOI: 10.1158/1541-7786.MCR-24-0444

Zachary J Walker, Katherine F Vaeth, Amber Baldwin, Denis J Ohlstrom, Lauren T Reiman, Kady A Dennis, Kate Matlin, Beau M Idler, Brett M Stevens, Neelanjan Mukherjee, Daniel W Sherbenou

{"title":"Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine Resistant Multiple Myeloma.","authors":"Zachary J Walker, Katherine F Vaeth, Amber Baldwin, Denis J Ohlstrom, Lauren T Reiman, Kady A Dennis, Kate Matlin, Beau M Idler, Brett M Stevens, Neelanjan Mukherjee, Daniel W Sherbenou","doi":"10.1158/1541-7786.MCR-24-0444","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0444","url":null,"abstract":"Protein homeostasis is critical to the survival of multiple myeloma (MM) cells. While this is targeted with proteasome inhibitors, mRNA translation inhibition has not entered trials. Recent work illustrates broad sensitivity MM cells to the translation inhibitor omacetaxine. We hypothesized that understanding how MM becomes resistant will lead to the development of drug combinations to prevent or delay relapse. We generated omacetaxine resistance in H929 and MM1S MM cell lines and compared them to parental lines. Resistant lines displayed decreased sensitivity to omacetaxine, with EC50 > 100 nM, compared to parental sensitivity of 24-54 nM. Since omacetaxine inhibits protein synthesis, we performed both RNA-sequencing and ribosome profiling (Ribo-seq) to identify shared and unique regulatory strategies of resistance. Transcripts encoding translation factors and containing Terminal OligoPyrimidine (TOP) sequence in their 5' UTR were translationally upregulated in both resistant cell lines. The mTOR pathway promotes the translation of TOP motif containing mRNAs. Indeed, mTOR inhibition with Torin 1 restored partial sensitivity to omacetaxine in both resistant cell lines. The combination was synergistic in omacetaxine naïve MM cell lines, and a combination effect was observed in vivo. Primary MM cells from patient samples were also sensitive to the combination. These results provide a rational approach for omacetaxine-based combination in patients with multiple myeloma, which have historically shown better responses to multi-agent regimens. Implications: Through the use of ribosome profiling, our findings indicate mTOR inhibition as a novel combination therapy for partnering with the translation inhibitor omacetaxine in the treatment of multiple myeloma.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567016","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

METTL3-Mediated m6A Modification Regulates the Polycomb Repressive Complex 1 Components BMI1 and RNF2 in Hepatocellular Carcinoma Cells. mettl3介导的m6A修饰调节肝癌细胞中多梳抑制复合体1 （PRC1）成分BMI1和RNF2。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0362

Weina Chen, Jinqiang Zhang, Wenbo Ma, Nianli Liu, Tong Wu

{"title":"METTL3-Mediated m6A Modification Regulates the Polycomb Repressive Complex 1 Components BMI1 and RNF2 in Hepatocellular Carcinoma Cells.","authors":"Weina Chen, Jinqiang Zhang, Wenbo Ma, Nianli Liu, Tong Wu","doi":"10.1158/1541-7786.MCR-24-0362","DOIUrl":"10.1158/1541-7786.MCR-24-0362","url":null,"abstract":"Methyltransferase-like 3 (METTL3) is a primary RNA methyltransferase that catalyzes N6-methyladenosine (m6A) modification. The current study aims to further delineate the effect and mechanism of METTL3 in hepatocellular carcinoma (HCC). By using a murine model of hepatocellular cancer development induced via hydrodynamic tail vein injection, we showed that METTL3 enhanced HCC development. In cultured human HCC cell lines (Huh7 and PLC/PRF/5), we observed that stable knockdown of METTL3 by short hairpin RNA significantly decreased tumor cell proliferation, colony formation, and invasion, in vitro. When Huh7 and PLC/PRF/5 cells with short hairpin RNA knockdown of METTL3 were inoculated into the livers of SCID mice, we found that METTL3 knockdown significantly inhibited the growth of HCC xenograft tumors. These findings establish METTL3 as an important oncogene in HCC. Through m6A sequencing, RNA sequencing, and subsequent validation studies, we identified BMI1 and RNF2, two key components of the polycomb repressive complex 1, as direct downstream targets of METTL3-mediated m6A modification in HCC cells. Our data indicated that METTL3 catalyzed m6A modification of BMI1 and RNF2 mRNAs which led to increased mRNA stability via the m6A reader proteins IGF2BP1/2/3. Furthermore, we showed that the METTL3 inhibitor, STM2457, significantly inhibited HCC cell growth in vitro and in mice. Collectively, this study provides novel evidence that METTL3 promotes HCC development and progression through m6A modification of BMI1 and RNF2. Our findings suggest that the METTL3-m6A-BMI1/RNF2 signaling axis may represent a new therapeutic target for the treatment of HCC. Implications: The METTL3-m6A-BMI1/RNF2 signaling axis promotes HCC development and progression.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"190-201"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770623","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

Stress and Obesity Signaling Converge on CREB Phosphorylation to Promote Pancreatic Cancer. 应激和肥胖信号汇聚在CREB磷酸化上促进胰腺癌。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0785

Xiaoying Sun, Yaroslav Teper, James Sinnett-Smith, Mineh Markarian, O Joe Hines, Gang Li, Guido Eibl, Enrique Rozengurt

{"title":"Stress and Obesity Signaling Converge on CREB Phosphorylation to Promote Pancreatic Cancer.","authors":"Xiaoying Sun, Yaroslav Teper, James Sinnett-Smith, Mineh Markarian, O Joe Hines, Gang Li, Guido Eibl, Enrique Rozengurt","doi":"10.1158/1541-7786.MCR-24-0785","DOIUrl":"10.1158/1541-7786.MCR-24-0785","url":null,"abstract":"One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the β-adrenergic receptor agonist isoproterenol rapidly stimulate cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation at Ser133 in human PDAC cells. Exposure to the nonselective β-adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551, blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser133. Mechanistically, norepinephrine induced CREB phosphorylation at Ser133 via PKA, whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D. Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet that promotes early PDAC development were subjected to social isolation stress. We show that social isolation stress induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia) in KC mice subjected to an obesogenic high fat, calorie diet. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"236-249"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11875952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789513","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

Gut Microbiota-Mediated hsa_circ_0126925 Targets BCAA Metabolic Enzyme BCAT2 to Exacerbate Colorectal Cancer Progression. 肠道菌群介导的hsa_circ_0126925靶向BCAA代谢酶BCAT2，加速结直肠癌进展。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0434

Huihui Yao, Jiancheng Xu, Aina Zhou, Danyang Shen, Qiuchen Dong, Xiaodong Yang, Mengyu Li, Xiuwei Mi, Yang Lu, Runze Zhong, Xinyu Shi, Qingliang Tai, Guoliang Chen, Bo Shi, Liang Sun, Diyuan Zhou, Yizhou Yao, Songbing He

{"title":"Gut Microbiota-Mediated hsa_circ_0126925 Targets BCAA Metabolic Enzyme BCAT2 to Exacerbate Colorectal Cancer Progression.","authors":"Huihui Yao, Jiancheng Xu, Aina Zhou, Danyang Shen, Qiuchen Dong, Xiaodong Yang, Mengyu Li, Xiuwei Mi, Yang Lu, Runze Zhong, Xinyu Shi, Qingliang Tai, Guoliang Chen, Bo Shi, Liang Sun, Diyuan Zhou, Yizhou Yao, Songbing He","doi":"10.1158/1541-7786.MCR-24-0434","DOIUrl":"10.1158/1541-7786.MCR-24-0434","url":null,"abstract":"Recent evidence indicates that a high-fat diet can promote tumor development, especially colorectal cancer, by influencing the microbiota. Regulatory circular RNA (circRNA) plays an important role in modulating host-microbe interactions; however, the specific mechanisms by which circRNAs influence cancer progression by regulating these interactions remain unclear. Here, we report that consumption of a high-fat diet modulates the microbiota by specifically upregulating the expression of the noncoding RNA hsa_circ_0126925 (herein, referred to as circ_0126925) in colorectal cancer. Acting as a scaffold, circ_0126925 hinders the recruitment of the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) to branched-chain amino acid transaminase 2 (BCAT2), leading to reduced degradation of BCAT2. This reduction in targeted degradation of BCAT2 can protect tumors from limited branched-chain amino acid (BCAA) interference by improving the metabolism of BCAAs in colorectal cancer. Taken together, these data demonstrate that circ_0126925 plays a critical role in promoting the progression of colorectal cancer by maintaining BCAA metabolism and provide insight into the functions and crosstalk of circ_0126925 in host-microbe interactions in colorectal cancer. Implications: This study preliminarily confirms that circRNAs do indeed respond to microbiota/microbial metabolites, providing further evidence for the potential development of circRNAs as diagnostic tools and/or therapeutic agents to alleviate microbiome-related pathology in humans.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"202-218"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789511","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

Cells in the Polyaneuploid Cancer Cell State Are Prometastatic. 多非整倍体癌细胞状态的细胞是前转移的。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0689

Mikaela M Mallin, Louis T A Rolle, Michael J Schmidt, Shilpa Priyadarsini Nair, Amado J Zurita, Peter Kuhn, James Hicks, Kenneth J Pienta, Sarah R Amend

{"title":"Cells in the Polyaneuploid Cancer Cell State Are Prometastatic.","authors":"Mikaela M Mallin, Louis T A Rolle, Michael J Schmidt, Shilpa Priyadarsini Nair, Amado J Zurita, Peter Kuhn, James Hicks, Kenneth J Pienta, Sarah R Amend","doi":"10.1158/1541-7786.MCR-24-0689","DOIUrl":"10.1158/1541-7786.MCR-24-0689","url":null,"abstract":"Our research aims to understand the adaptive-ergo potentially metastatic-responses of prostate cancer to changing microenvironments. Emerging evidence implicates a role of the polyaneuploid cancer cell (PACC) state in metastasis, positing the PACC state as capable of conferring metastatic competency. Mounting in vitro evidence supports increased metastatic potential of cells in the PACC state. Additionally, our recent retrospective study revealed that PACC presence in patient prostate tumors at the time of radical prostatectomy was predictive of future metastasis. To test for a causative relationship between PACC state biology and metastasis in prostate cancer, we leveraged a novel method designed for flow cytometric detection of circulating tumor cells (CTC) and disseminated tumor cells (DTC) from animal models. This approach provides both quantitative and qualitative information about the number and PACC status of recovered CTCs and DTCs. Specifically, we applied this approach to the analysis of subcutaneous, caudal artery, and intracardiac murine models. Collating data from all models, we found that 74% of recovered CTCs and DTCs were in the PACC state. Furthermore, in vivo colonization assays proved that PACC populations can regain proliferative capacity at metastatic sites. Additional in vitro analyses revealed a PACC-specific partial epithelial-to-mesenchymal transition phenotype and a prometastatic secretory profile, together providing preliminary evidence of prometastatic mechanisms specific to the PACC state. Implications: Considering that many anticancer agents induce the PACC state, our data position the increased metastatic competency of PACC state cells as an important unforeseen ramification of neoadjuvant regimens, which may help explain clinical correlations between chemotherapy and metastatic progression.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"219-235"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801586","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

Tumor-Derived EBV-miR-BART2-5p Promotes Nasopharyngeal Carcinoma Metastasis by Inducing Premetastatic Endothelial Cell Pyroptosis. 肿瘤衍生的EBV-miR-BART2-5p通过诱导转移前内皮细胞热解促进鼻咽癌转移。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0165

Xingrui Chen, Qiqi Li, Xiaoyan Fu, Jike Li, Jun Deng, Qianbing Zhang, Mengying Qiu, Xiaoming Lyu, Linbo Cai, Hainan Li, Xin Li, Kaitai Yao, Jiahong Wang, Zhongxi Huang, Liang Chen, Jiangyu Zhang, Dengke Li

{"title":"Tumor-Derived EBV-miR-BART2-5p Promotes Nasopharyngeal Carcinoma Metastasis by Inducing Premetastatic Endothelial Cell Pyroptosis.","authors":"Xingrui Chen, Qiqi Li, Xiaoyan Fu, Jike Li, Jun Deng, Qianbing Zhang, Mengying Qiu, Xiaoming Lyu, Linbo Cai, Hainan Li, Xin Li, Kaitai Yao, Jiahong Wang, Zhongxi Huang, Liang Chen, Jiangyu Zhang, Dengke Li","doi":"10.1158/1541-7786.MCR-24-0165","DOIUrl":"10.1158/1541-7786.MCR-24-0165","url":null,"abstract":"Extravasation is a key step in tumor metastasis. Epstein‒Barr virus plays a crucial role in nasopharyngeal carcinoma (NPC) metastasis. However, the functions and molecular mechanisms of Epstein‒Barr virus during tumor cell extravasation remain unclear. Here, we showed that the expression of pyroptosis-associated proteins is greater in the endothelial cells of metastatic NPC tissues than in those of nontumor tissues exosomes derived from NPC cells promoted endothelial cell pyroptosis, vascular permeability, and tumor cell extravasation. Moreover, we found that BART2-5p is abundant in serum exosomes from patients with NPC metastasis and in NPC cells and that it regulates endothelial cell pyroptosis in premetastatic organs via MRE11A. Exosomes containing a BART2-5p inhibitor and AAV-MRE11A attenuated endothelial cell pyroptosis and tumor metastasis. Moreover, in the endothelial cells of metastatic tissues from patients with NPC, the BART2-5p level was positively associated with pyroptosis-related protein expression. Collectively, our findings suggest that exosomal BART2-5p is involved in premetastatic niche formation, identifying secreted BART2-5p as a potential therapeutic target for NPC metastasis. Implications: The finding that secreted BART2-5p is involved in premetastatic niche formation may aid the development of a potential therapeutic target for NPC metastasis.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"250-262"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638741","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

Cross-talk between WNT Signaling and Ferroptosis in Cancer. 癌症中WNT信号与铁下垂之间的串扰。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-03-03 DOI: 10.1158/1541-7786.MCR-24-0880

Zheng Wang, Zhixiang Zhang, Yunhui Yue, Yifan Hou, Yujia Cao, Changsheng Guo, Xiaobo Nie, Junqing Hou

{"title":"Cross-talk between WNT Signaling and Ferroptosis in Cancer.","authors":"Zheng Wang, Zhixiang Zhang, Yunhui Yue, Yifan Hou, Yujia Cao, Changsheng Guo, Xiaobo Nie, Junqing Hou","doi":"10.1158/1541-7786.MCR-24-0880","DOIUrl":"10.1158/1541-7786.MCR-24-0880","url":null,"abstract":"Cancer remains one of the most formidable challenges in the medical field in this century, largely because of its poorly understood pathogenesis. Fortunately, recent advancements in the understanding of cancer pathogenesis have helped identify more therapeutic targets for improved treatment outcomes. The WNT signaling pathways are highly conserved cascades that participate in diverse physiologic processes, such as embryonic development, tissue homeostasis, and tissue regeneration. Ferroptosis, a unique iron-dependent form of cell death that is distinct from apoptosis, is driven by lipid peroxidation and excessive reactive oxygen species production. Emerging evidence shows that the dysregulation of WNT signaling pathways and ferroptosis, as well as their intricate cross-talk, plays crucial roles in cancer progression and therapeutic resistance, indicating their potential as targets for cancer therapies. This review provides a comprehensive overview of the current understanding of the cross-talk between WNT signaling pathways and ferroptosis in the pathogenesis and progression of cancer, with a specific focus on the regulatory role of the canonical WNT cascade in cancer-related ferroptosis. In addition, we discuss the pharmacologic mechanisms of current strategies that inhibit canonical WNT signaling and/or induce ferroptosis in cancer treatment. We propose that combining canonical WNT pathway inhibitors and ferroptosis inducers with current therapies represents a promising therapeutic strategy for personalized cancer treatment.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"175-189"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951530","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

TIPE Inhibits Ferroptosis in Colorectal Cancer Cells by Regulating MGST1/ALOX5. TIPE 通过调控 MGST1/ALOX5 抑制结直肠癌细胞的铁突变。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-02-06 DOI: 10.1158/1541-7786.MCR-24-0433

Changxiu Yan, Shengnan Yu, Jing Zhang, Zhen Li, Zeyang Lin, Shiying Zhang, Haoyang Li, Zhijian Ye, Jiyi Huang, Yuhan Ye, Guohong Zhuang

{"title":"TIPE Inhibits Ferroptosis in Colorectal Cancer Cells by Regulating MGST1/ALOX5.","authors":"Changxiu Yan, Shengnan Yu, Jing Zhang, Zhen Li, Zeyang Lin, Shiying Zhang, Haoyang Li, Zhijian Ye, Jiyi Huang, Yuhan Ye, Guohong Zhuang","doi":"10.1158/1541-7786.MCR-24-0433","DOIUrl":"10.1158/1541-7786.MCR-24-0433","url":null,"abstract":"TIPE is a protein highly expressed in various cancers that promotes ferroptosis in colorectal cancer cells. Ferroptosis is a nonapoptotic cell death caused by lipid peroxidation, and microsomal glutathione transferase 1 (MGST1) is a critical enzyme that resists lipid peroxidation. This study explored how TIPE regulates MGST1 expression to inhibit ferroptosis and promote colorectal cancer proliferation. TIPE was highly expressed in colorectal cancer tissues and positively correlated with the proliferation of human colorectal cancer cells. We measured levels of reactive oxygen species and lipid reactive oxygen species in colorectal cancer cells with differential expression of TIPE and detected ferroptosis using transmission electron microscopy. Bioinformatics analysis revealed a positive correlation of expression patterns between TIPE and MGST1 in colorectal cancer. TIPE regulated the expression of MGST1 by activating the phosphorylation of ERK1/2. Coimmunoprecipitation revealed binding between MGST1 and ALOX5. This binding inhibited the phosphorylation of ALOX5, inhibiting ferroptosis and promoting the proliferation of colorectal cancer cells. A tumor formation experiment in nude mice supported our findings that TIPE regulates the proliferation of colorectal cancer by regulating ferroptosis. Implications: TIPE inhibits colorectal cancer ferroptosis via an MGST1-ALOX5 interaction to promote colorectal cancer proliferation. These findings suggest future colorectal cancer treatment strategies.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"143-154"},"PeriodicalIF":4.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605460","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}

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