Molecular Cancer Research最新文献_第3页

Identifying and targeting key driver genes for collagen production within the 11q13/14 breast cancer amplicon. 鉴定和靶向11q13/14乳腺癌扩增子中胶原蛋白产生的关键驱动基因。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-01-21 DOI: 10.1158/1541-7786.MCR-24-0331

Daniela Araiza-Olivera, Tatiana Y Prudnikova, Cristina Uribe-Alvarez, Kathy Q Cai, Janusz Franco-Barraza, Jesus M Dones, Ronald T Raines, Jonathan Chernoff

{"title":"Identifying and targeting key driver genes for collagen production within the 11q13/14 breast cancer amplicon.","authors":"Daniela Araiza-Olivera, Tatiana Y Prudnikova, Cristina Uribe-Alvarez, Kathy Q Cai, Janusz Franco-Barraza, Jesus M Dones, Ronald T Raines, Jonathan Chernoff","doi":"10.1158/1541-7786.MCR-24-0331","DOIUrl":"10.1158/1541-7786.MCR-24-0331","url":null,"abstract":"Breast cancers of the IntClust-2 type, characterized by amplification of a small portion of chromosome 11, have a median survival of only five years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study we used a gene editing method to knock out, one by one, each of 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1, we identified two different genes (SERPINH1 and P4HA3), that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function on IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers. Implications: Breast cancers with 11q13/14 chromosomal amplifications may be vulnerable to inhibitors of collagen synthesis.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008965","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

Intracellular Retention of Estradiol is Mediated by GRAM Domain-Containing Protein ASTER-B in Breast Cancer Cells. 乳腺癌细胞中含有GRAM结构域的蛋白ASTER-B介导雌二醇的细胞内滞留。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-01-13 DOI: 10.1158/1541-7786.MCR-24-0533

Hyung Bum Kim, W Lee Kraus

{"title":"Intracellular Retention of Estradiol is Mediated by GRAM Domain-Containing Protein ASTER-B in Breast Cancer Cells.","authors":"Hyung Bum Kim, W Lee Kraus","doi":"10.1158/1541-7786.MCR-24-0533","DOIUrl":"10.1158/1541-7786.MCR-24-0533","url":null,"abstract":"Elevated blood levels of estrogens are associated with poor prognosis in estrogen receptor-positive (ER+) breast cancers, but the relationship between circulating blood hormone levels and intracellular hormone concentrations are not well characterized. We observed that MCF-7 cells treated acutely with 17β-estradiol (E2) retain a substantial amount of the hormone even upon removal of the hormone from the culture medium. Moreover, global patterns of E2-dependent gene expression are sustained for hours after acute E2 treatment and hormone removal. While circulating E2 is sequestered by sex hormone binding globulin (SHBG), the potential mechanisms of intracellular E2 retention are poorly understood. We found that a mislocalization of a steroid-binding GRAM-domain containing protein, ASTER-B, to the nucleus, which is observed in a subset of breast cancer patients, is associated with higher cellular E2 retention. Accumulation and retention of E2 are related to the steroidal properties of E2, and require nuclear localization and steroid binding by ASTER-B, as shown using a panel of mutant ASTER-B proteins. Finally, we observed that nuclear ASTER-B-mediated E2 retention is required for sustained hormone-induced ERalpha chromatin occupancy at enhancers and gene expression, as well as subsequent cell growth responses. Our results add intracellular hormone retention as a mechanism controlling E2-dependent gene expression and downstream biological outcomes. Implications: Mislocalized nuclear ASTER-B, which binds estradiol to support the functions of ER, can provide an alternate means of enhancing the biological effects of E2 in breast cancers and may be a potential therapeutic target that addresses multiple aspects of estrogen bioavailability.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971681","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

Exploring B7-H4's role in prostate cancer dormancy post-androgen deprivation therapy: extracellular matrix interactions and therapeutic opportunities. 探讨B7-H4在前列腺癌雄激素剥夺治疗后休眠中的作用：细胞外基质相互作用和治疗机会。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-01-07 DOI: 10.1158/1541-7786.MCR-24-0958

Ning Kang, Hui Xue, Nelson K Y Wong, Yen-Yi Lin, Adam Classen, Rebecca Wu, Htoo Zarni Oo, Xin Dong, Angela Trinh, Dong Lin, Mads Daugaard, Christopher Ong, Colin Collins, Martin Gleave, Yuzhuo Wang

{"title":"Exploring B7-H4's role in prostate cancer dormancy post-androgen deprivation therapy: extracellular matrix interactions and therapeutic opportunities.","authors":"Ning Kang, Hui Xue, Nelson K Y Wong, Yen-Yi Lin, Adam Classen, Rebecca Wu, Htoo Zarni Oo, Xin Dong, Angela Trinh, Dong Lin, Mads Daugaard, Christopher Ong, Colin Collins, Martin Gleave, Yuzhuo Wang","doi":"10.1158/1541-7786.MCR-24-0958","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0958","url":null,"abstract":"Prostate cancer (PCa) is mainly managed with androgen deprivation therapy (ADT), but this often leads to a dormant state and subsequent relapse as lethal castration-resistant prostate cancer (CRPC). Using our unique PCa patient-derived xenograft (PDX) dormancy models, we investigated this critical dormant phase and discovered a selective increase in B7-H4 expression during the dormancy period following mouse host castration. This finding is supported by observations in clinical specimens of PCa patients treated with ADT. Differential expression analyses revealed the enrichment of extracellular matrix (ECM)-cell interaction pathways in B7-H4-positive cells. Functional assays demonstrated a crucial role of B7-H4 in maintaining dormancy within the ECM niche. Specifically, B7-H4 expression in LNCaP cells reduced proliferation within dormant ECM in vitro and significantly delayed relapse in castrated hosts in vivo. These results shed light on the dynamic regulation of B7-H4 during PCa dormancy and underscore its potential as a therapeutic target for preventing CRPC relapse. Implications: Our study identified membranous B7-H4 expression during ADT-induced dormancy, highlighting its potential as a therapeutic target for managing dormant prostate cancer and preventing fatal CRPC relapse.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951495","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

Loss of PI5P4Kα Slows the Progression of a Pten Mutant Basal Cell Model of Prostate Cancer. 缺失 PI5P4Kα 可减缓前列腺癌 Pten 突变基底细胞模型的进展。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-01-02 DOI: 10.1158/1541-7786.MCR-24-0290

Joanna Triscott, Marika Lehner, Andrej Benjak, Matthias Reist, Brooke M Emerling, Charlotte K Y Ng, Simone de Brot, Mark A Rubin

{"title":"Loss of PI5P4Kα Slows the Progression of a Pten Mutant Basal Cell Model of Prostate Cancer.","authors":"Joanna Triscott, Marika Lehner, Andrej Benjak, Matthias Reist, Brooke M Emerling, Charlotte K Y Ng, Simone de Brot, Mark A Rubin","doi":"10.1158/1541-7786.MCR-24-0290","DOIUrl":"10.1158/1541-7786.MCR-24-0290","url":null,"abstract":"Although early prostate cancer depends on the androgen receptor signaling pathway, which is predominant in luminal cells, there is much to be understood about the contribution of epithelial basal cells in cancer progression. Herein, we observe cell type-specific differences in the importance of the metabolic enzyme phosphatidylinositol 5-phosphate 4-kinase alpha (PI5P4Kα; gene name PIP4K2A) in the prostate epithelium. We report the development of a basal cell-specific genetically engineered mouse model targeting Pip4k2a alone or in combination with the tumor suppressor phosphatase and tensin homolog (Pten). PI5P4Kα is enriched in basal cells, and no major histopathologic changes were detectable following gene deletion. Notably, the combined loss of Pip4k2a slowed the development of Pten mutant mouse prostatic intraepithelial neoplasia. Through the inclusion of a lineage tracing reporter, we utilize single-cell RNA sequencing to evaluate changes resulting from in vivo downregulation of Pip4k2a and characterize cell populations influenced in the established Probasin-Cre- and cytokeratin 5-Cre-driven genetically engineered mouse model. Transcriptomic pathway analysis points toward the disruption of lipid metabolism as a mechanism for reduced tumor progression. This was functionally supported by shifts of carnitine lipids in LNCaP prostate cancer cells treated with siPIP4K2A. Overall, these data nominate PI5P4Kα as a target for PTEN mutant prostate cancer. Implications: PI5P4Kα is enriched in prostate basal cells, and its targeted loss slows the progression of a model of advanced prostate cancer.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"33-45"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392035","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 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 : 2025-01-02 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":"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. 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 database. Deficiencies in either base excision repair due to the absence of Nei-like DNA glycosylase 1 (NEIL1) or nucleotide excision repair due to the absence of xeroderma complementation group A protein (XPA) contribute to hepatocellular carcinomas 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 the 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 base excision repair and nucleotide excision repair deficiencies.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"46-58"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695181/pdf/","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":"OA","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 : 2025-01-02 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 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 imaging of formalin-fixed, paraffin embedded 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 the 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 prostate cancer 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":"59-70"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694069/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gram-Negative Microflora Dysbiosis Facilitates Tumor Progression and Immune Evasion by Activating the CCL3/CCL5-CCR1-MAPK-PD-L1 Pathway in Esophageal Squamous Cell Carcinoma. 革兰氏阴性微生物菌群失调通过激活食管鳞状细胞癌中的 CCL3/CCL5-CCR1-MAPK-PD-L1 通路促进肿瘤进展和免疫逃避

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-01-02 DOI: 10.1158/1541-7786.MCR-24-0451

Huiqin Yang, Jiahao Cai, Xiaolong Huang, Cheng Zhan, Chunlai Lu, Jie Gu, Teng Ma, Hongyu Zhang, Tao Cheng, Fengkai Xu, Di Ge

{"title":"Gram-Negative Microflora Dysbiosis Facilitates Tumor Progression and Immune Evasion by Activating the CCL3/CCL5-CCR1-MAPK-PD-L1 Pathway in Esophageal Squamous Cell Carcinoma.","authors":"Huiqin Yang, Jiahao Cai, Xiaolong Huang, Cheng Zhan, Chunlai Lu, Jie Gu, Teng Ma, Hongyu Zhang, Tao Cheng, Fengkai Xu, Di Ge","doi":"10.1158/1541-7786.MCR-24-0451","DOIUrl":"10.1158/1541-7786.MCR-24-0451","url":null,"abstract":"Gram-negative (G-) microflora dysbiosis occurs in multiple digestive tumors and is found to be the dominant microflora in the esophageal squamous cell carcinoma (ESCC) microenvironment. The continuous stimulation of G- bacterium metabolites may cause tumorigenesis and reshape the microimmune environment in ESCC. However, the mechanism of G- bacilli causing immune evasion in ESCC remains underexplored. We identified CC chemokine receptor 1 (CCR1) as a tumor-indicating gene in ESCC. Interestingly, expression levels of CCR1 and PD-L1 were mutually upregulated after G- bacilli metabolite lipopolysaccharide stimulation. First, we found that CCR1 high expression levels were associated with poor overall survival in ESCC. Importantly, we found that high levels of CCR1 expression upregulated PD-L1 expression by activating MAPK phosphorylation in ESCC and induced tumor malignant behavior. Finally, we found that T-cell exhaustion and cytotoxicity suppression were associated with CCR1 expression in ESCC, which were decreased after CCR1 inhibiting. Our work identifies CCR1 as a potential immune check point regulator of PD-L1 and may cause T-cell exhaustion and cytotoxicity suppression in ESCC microenvironment and highlights the potential value of CCR1 as a therapeutic target of immunotherapy. Implications: The esophageal microbial environment and its metabolites significantly affect the outcome of immunotherapy for ESCC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"71-85"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350768","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

B-type Plexins Regulate Mitosis via RanGTPase. B 型丛集蛋白通过 RanGTPase 调节有丝分裂。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2025-01-02 DOI: 10.1158/1541-7786.MCR-23-0836

Nicholus Mukhwana, Ritu Garg, Abul Azad, Alexandria R Mitchell, Magali Williamson

{"title":"B-type Plexins Regulate Mitosis via RanGTPase.","authors":"Nicholus Mukhwana, Ritu Garg, Abul Azad, Alexandria R Mitchell, Magali Williamson","doi":"10.1158/1541-7786.MCR-23-0836","DOIUrl":"10.1158/1541-7786.MCR-23-0836","url":null,"abstract":"Aberrant mitosis can result in aneuploidy and cancer. The small GTPase, Ras-related nuclear protein (Ran), is a key regulator of mitosis. B-type plexins regulate Ran activity by acting as RanGTPase-activating proteins and have been implicated in cancer progression. However, whether B-type plexins have a role in mitosis has not so far been investigated. We show here that Plexin B1 functions in the control of mitosis. Depletion of Plexin B1 affects mitotic spindle assembly, significantly delaying anaphase. This leads to mitotic catastrophe in some cells and prolonged application of the spindle assembly checkpoint. Plexin B1 depletion also promoted acentrosomal microtubule nucleation and defects in spindle pole refocusing and increased the number of cells with multipolar or aberrant mitotic spindles. An increase in lagging chromosomes or chromosomal bridges at anaphase was also found upon Plexin B1 depletion. Plexin B1 localizes to the mitotic spindle in dividing cells. The mitotic defects observed upon Plexin B1 depletion were rescued by an RCC1 inhibitor, indicating that Plexin B1 signals, via Ran, to affect mitosis. These errors in mitosis generated multinucleate cells and nuclei of altered morphology and abnormal karyotype. Furthermore, semaphorin 4D treatment increased the percentage of cells with micronuclei, precursors of chromothripsis. Implications: Defects in B-type plexins may contribute to the well-established role of plexins in cancer progression by inducing chromosomal instability.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"8-19"},"PeriodicalIF":4.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971524","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

Crosstalk 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 : 2024-12-30 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":"Crosstalk 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":"https://doi.org/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 due to 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 physiological 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 (ROS) production. Emerging evidence shows that the dysregulation of WNT signaling pathways and ferroptosis, as well as their intricate crosstalk, 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 crosstalk 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 pharmacological mechanisms of current strategies that inhibit canonical WNT signaling and/or induce ferroptosis in cancer treatment. We propose that combining canonical WNT pathway inhibitors with ferroptosis inducers and current therapies represents a promising therapeutic strategy for personalized cancer treatment.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-30","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

Bmal1-mediated circadian MELK expression potentiates MELK inhibitor chronotherapy for esophageal cancer. bmal1介导的MELK昼夜表达增强了MELK抑制剂对食管癌的时间治疗。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-12-19 DOI: 10.1158/1541-7786.MCR-24-0498

Boning Zeng, Chao Sun, Qian Tang, Nan Li, Siying Chen, Yili Yang, Xiao Wang, Shaoxiang Wang

{"title":"Bmal1-mediated circadian MELK expression potentiates MELK inhibitor chronotherapy for esophageal cancer.","authors":"Boning Zeng, Chao Sun, Qian Tang, Nan Li, Siying Chen, Yili Yang, Xiao Wang, Shaoxiang Wang","doi":"10.1158/1541-7786.MCR-24-0498","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0498","url":null,"abstract":"Esophageal squamous cell carcinoma (ESCC) remains a global health challenge. Circadian clock and Maternal embryonic leucine zipper kinase (MELK) play a key role in tumorigenesis. However, a link between circadian clock dysregulation and MELK function in the occurrence and development of ESCC remains elusive. Here, In the in vivo and in vitro systems, we found for the first time that MELK exhibits pronounced circadian rhythms expression in mice esophageal tissue, xenograft model and human ESCC cells. The diurnal differences expression between peak (ZT0) and trough (ZT12) points in normal esophageal tissue is nearly 10-fold. Circadian expression of MELK in ESCC cells was regulated by Bmal1 through binding to the MELK promoter. Supporting this, the levels of MELK were increased significantly in ESCC patients, and was accompanied with altered expression of core clock genes, especially, Bmal1 is prominently upregulated. Most importantly, Bmal1-deleted eliminated the rhythmic expression of MELK, while knockdown of other core genes had no effect on MELK expression. Furthermore, in nude mice with transplanted tumor, the anticancer effect of OTS167 at ZT0 administration is twice that of ZT12. Implications: Our findings suggest that MELK represents a therapeutic target, and can as a regulator of circadian control ESCC growth, with these findings advance our understanding of the clinical potential of chronotherapy and the importance of time-based MELK inhibition in cancer treatment.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854491","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