Molecular Cancer Research最新文献_第5页

MLLT6/ATF2 axis restrains breast cancer progression by driving DDIT3/4 expression. MLLT6/ATF2轴通过驱动DDIT3/4的表达抑制乳腺癌的进展。

IF 5.2 2区医学

Molecular Cancer Research Pub Date : 2024-05-17 DOI: 10.1158/1541-7786.MCR-23-0648

Qing Yu, Jiayi Zhao, Anli Yang, Xiangxin Li

{"title":"MLLT6/ATF2 axis restrains breast cancer progression by driving DDIT3/4 expression.","authors":"Qing Yu, Jiayi Zhao, Anli Yang, Xiangxin Li","doi":"10.1158/1541-7786.MCR-23-0648","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-23-0648","url":null,"abstract":"Epigenetic deregulation is strongly associated with tumour progression. The identification of natural tumour suppressors to overcome cancer metastasis is urgent for cancer therapy. We investigate whether myeloid/lymphoid or mixed-lineage leukaemia translocated (MLLT) family members contribute to breast cancer progression and found that high MLLT6 expression predicted a better prognosis and that gradually decreased MLLT6 expression was accompanied by breast cancer malignancy. MLLT6 was downregulated by hypoxia-induced enrichment of DNMT1 at the MLLT6 promoter. The results of in vitro functional experiments indicated that MLLT6 depletion promoted colony formation and cell migration, probably by hampering apoptosis. RNA profiling revealed that the apoptotic pathway was downregulated following stable knockdown of MLLT6. DNA damage-inducible transcript 3/4 (DDIT3/4) were among the top 10 downregulated genes and may have expression patterns similar to that of MLLT6. Restoring DDIT3/4 expression in cells with MLLT6 depletion blocked colony formation and cell migration and attenuated the successful colonization of breast cancer cells in vivo. We also determined that the transcription factor activating transcription factor 2 (ATF2) is a binding partner of MLLT6 and participates in the MLLT6/ATF2 axis, which was reinforced by inhibition of AKT signalling, in turn inducing DDIT3/4 expression by establishing an active chromatin structure at the DDIT3/4 gene promoters. Because MLLT6 promotes breast cancer cell apoptosis by inducing DDIT3/4 expression during metastasis, it could be a novel tumour suppressor. Implications: Control of MLLT6 expression via inhibition of PI3K/AKT kinase activity is a potential therapeutic approach for the management of metastatic breast cancer.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958589","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

Coregulation of NDC80 Complex Subunits Determines the Fidelity of the Spindle-Assembly Checkpoint and Mitosis. NDC80 复合物亚基的协同调控决定了纺锤体组装检查点和有丝分裂的保真度。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-05-02 DOI: 10.1158/1541-7786.MCR-23-0828

Sehong Kim, Thomas T Y Lau, Man Kit Liao, Hoi Tang Ma, Randy Y C Poon

{"title":"Coregulation of NDC80 Complex Subunits Determines the Fidelity of the Spindle-Assembly Checkpoint and Mitosis.","authors":"Sehong Kim, Thomas T Y Lau, Man Kit Liao, Hoi Tang Ma, Randy Y C Poon","doi":"10.1158/1541-7786.MCR-23-0828","DOIUrl":"10.1158/1541-7786.MCR-23-0828","url":null,"abstract":"NDC80 complex (NDC80C) is composed of four subunits (SPC24, SPC25, NDC80, and NUF2) and is vital for kinetochore-microtubule (KT-MT) attachment during mitosis. Paradoxically, NDC80C also functions in the activation of the spindle-assembly checkpoint (SAC). This raises an interesting question regarding how mitosis is regulated when NDC80C levels are compromised. Using a degron-mediated depletion system, we found that acute silencing of SPC24 triggered a transient mitotic arrest followed by mitotic slippage. SPC24-deficient cells were unable to sustain SAC activation despite the loss of KT-MT interaction. Intriguingly, our results revealed that other subunits of the NDC80C were co-downregulated with SPC24 at a posttranslational level. Silencing any individual subunit of NDC80C likewise reduced the expression of the entire complex. We found that the SPC24-SPC25 and NDC80-NUF2 subcomplexes could be individually stabilized using ectopically expressed subunits. The synergism of SPC24 downregulation with drugs that promote either mitotic arrest or mitotic slippage further underscored the dual roles of NDC80C in KT-MT interaction and SAC maintenance. The tight coordinated regulation of NDC80C subunits suggests that targeting individual subunits could disrupt mitotic progression and provide new avenues for therapeutic intervention.Implications: These results highlight the tight coordinated regulation of NDC80C subunits and their potential as targets for antimitotic therapies.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11063766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697861","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

SCUBE3 Exerts a Tumor-Promoting Effect in Tongue Squamous Cell Carcinoma by Promoting CEBPA Binding to the CCL2 Promoter. SCUBE3 通过促进 CEBPA 与 CCL2 启动子的结合，在舌鳞癌中发挥肿瘤促进作用。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-05-02 DOI: 10.1158/1541-7786.MCR-23-0038

Minhui Zhu, Yi Ma, Wei Wang, Meng Li, Shicai Chen, Fei Liu, Xiaoqiong Shi, Hongsen Bi, Chen Zhang, Fangfei Nie, Hongliang Zheng, Caiyun Zhang

{"title":"SCUBE3 Exerts a Tumor-Promoting Effect in Tongue Squamous Cell Carcinoma by Promoting CEBPA Binding to the CCL2 Promoter.","authors":"Minhui Zhu, Yi Ma, Wei Wang, Meng Li, Shicai Chen, Fei Liu, Xiaoqiong Shi, Hongsen Bi, Chen Zhang, Fangfei Nie, Hongliang Zheng, Caiyun Zhang","doi":"10.1158/1541-7786.MCR-23-0038","DOIUrl":"10.1158/1541-7786.MCR-23-0038","url":null,"abstract":"Tongue squamous cell carcinoma (TSCC) is the main pathologic subtype of oral cancer, and the current therapeutic effect is far from satisfactory. The signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) has been shown to be a tumor-promoting factor in several malignancies. However, little is known about the role of SCUBE3 in TSCC. In this study, we identified that SCUBE3 was highly expressed in TSCC. Clinically, high expression of SCUBE3 was positively associated with tumor stage and T stage of TSCC. Functionally, SCUBE3 silence remarkably restrained cell proliferation, migration, and invasion, induced apoptosis as well as cell cycle arrest in G2-phase, and weakened the tumorigenicity of TSCC cells in vivo. Mechanistically, SCUBE3 promoted the direct binding of CCAAT enhancer binding protein alpha (CEBPA) to C-C motif chemokine ligand 2 (CCL2) promoter in TSCC cells. Interestingly, CCL2 overexpression partially reversed the inhibitory effect of SCUBE3 deficiency on TSCC cell viability and migration. Moreover, STAT3 signaling contributed to CCL2-mediated phenotypes in TSCC cells.Implications: Our data revealed a tumor-promoting role for SCUBE3 in TSCC via the CEBPA/CCL2/STAT3 axis, which provided new insight into novel potential therapeutic target for TSCC.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139723479","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

Oncogenic GNAS Uses PKA-Dependent and Independent Mechanisms to Induce Cell Proliferation in Human Pancreatic Ductal and Acinar Organoids. 致癌基因 GNAS 利用 PKA 依赖性和独立机制诱导人胰腺导管和尖腺器官组织中的细胞增殖。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-05-02 DOI: 10.1158/1541-7786.MCR-23-0199

Ridhdhi Desai, Ling Huang, Raul S Gonzalez, Senthil K Muthuswamy

引用次数: 0

Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts. 揭示前列腺癌患者衍生异种移植物的全局蛋白质组和磷酸蛋白质组

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-05-02 DOI: 10.1158/1541-7786.MCR-23-0976

Zoi E Sychev, Abderrahman Day, Hannah E Bergom, Gabrianne Larson, Atef Ali, Megan Ludwig, Ella Boytim, Ilsa Coleman, Eva Corey, Stephen R Plymate, Peter S Nelson, Justin H Hwang, Justin M Drake

{"title":"Unraveling the Global Proteome and Phosphoproteome of Prostate Cancer Patient-Derived Xenografts.","authors":"Zoi E Sychev, Abderrahman Day, Hannah E Bergom, Gabrianne Larson, Atef Ali, Megan Ludwig, Ella Boytim, Ilsa Coleman, Eva Corey, Stephen R Plymate, Peter S Nelson, Justin H Hwang, Justin M Drake","doi":"10.1158/1541-7786.MCR-23-0976","DOIUrl":"10.1158/1541-7786.MCR-23-0976","url":null,"abstract":"Resistance to androgen-deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform into emergent aggressive variant prostate cancer (AVPC), which has neuroendocrine (NE)-like features. In this work, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflect and retain key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. We compared 15 NE versus 33 AdCa samples, which included six different PDX tumors for each group in biological replicates, and identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of concordance from PDX tumor-matched protein and mRNA revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa.Implications: Overall, our study highlights the importance of protein-based identification when compared with RNA and provides a rich resource of new and feasible targets for clinical assay development and in understanding the underlying biology of these tumors.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11063764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139723480","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

ROR2/Wnt5a Signaling Regulates Directional Cell Migration and Early Tumor Cell Invasion in Ovarian Cancer. ROR2/Wnt5a信号调节卵巢癌的定向细胞迁移和早期肿瘤细胞侵袭。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-05-02 DOI: 10.1158/1541-7786.MCR-23-0616

Whitney R Grither, Breanna Baker, Vasilios A Morikis, Ma Xenia G Ilagan, Katherine C Fuh, Gregory D Longmore

{"title":"ROR2/Wnt5a Signaling Regulates Directional Cell Migration and Early Tumor Cell Invasion in Ovarian Cancer.","authors":"Whitney R Grither, Breanna Baker, Vasilios A Morikis, Ma Xenia G Ilagan, Katherine C Fuh, Gregory D Longmore","doi":"10.1158/1541-7786.MCR-23-0616","DOIUrl":"10.1158/1541-7786.MCR-23-0616","url":null,"abstract":"Adhesion to and clearance of the mesothelial monolayer are key early events in metastatic seeding of ovarian cancer. ROR2 is a receptor tyrosine kinase that interacts with Wnt5a ligand to activate noncanonical Wnt signaling and has been previously shown to be upregulated in ovarian cancer tissue. However, no prior study has evaluated the mechanistic role of ROR2 in ovarian cancer. Through a cellular high-throughput genetic screen, we independently identified ROR2 as a driver of ovarian tumor cell adhesion and invasion. ROR2 expression in ovarian tumor cells serves to drive directed cell migration preferentially toward areas of high Wnt5a ligand, such as the mesothelial lined omentum. In addition, ROR2 promotes ovarian tumor cell adhesion and clearance of a mesothelial monolayer. Depletion of ROR2, in tumor cells, reduces metastatic tumor burden in a syngeneic model of ovarian cancer. These findings support the role of ROR2 in ovarian tumor cells as a critical factor contributing to the early steps of metastasis. Therapeutic targeting of the ROR2/Wnt5a signaling axis could provide a means of improving treatment for patients with advanced ovarian cancer.Implications: This study demonstrates that ROR2 in ovarian cancer cells is important for directed migration to the metastatic niche and provides a potential signaling axis of interest for therapeutic targeting in ovarian cancer.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11065611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139707380","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

An Endosomal Acid-Regulatory Feedback System Rewires Cytosolic cAMP Metabolism and Drives Tumor Progression. 内质体酸调节反馈系统重构了细胞膜 cAMP 代谢，并推动了肿瘤进展。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-05-02 DOI: 10.1158/1541-7786.MCR-23-0606

Hari Prasad, Susmita Mandal, John Kandam Kulathu Mathew, Aparna Cherukunnath, Atchuta Srinivas Duddu, Mallar Banerjee, Harini Ramani, Ramray Bhat, Mohit Kumar Jolly, Sandhya S Visweswariah

{"title":"An Endosomal Acid-Regulatory Feedback System Rewires Cytosolic cAMP Metabolism and Drives Tumor Progression.","authors":"Hari Prasad, Susmita Mandal, John Kandam Kulathu Mathew, Aparna Cherukunnath, Atchuta Srinivas Duddu, Mallar Banerjee, Harini Ramani, Ramray Bhat, Mohit Kumar Jolly, Sandhya S Visweswariah","doi":"10.1158/1541-7786.MCR-23-0606","DOIUrl":"10.1158/1541-7786.MCR-23-0606","url":null,"abstract":"Although suppressed cAMP levels have been linked to cancer for nearly five decades, the molecular basis remains uncertain. Here, we identify endosomal pH as a novel regulator of cytosolic cAMP homeostasis and a promoter of transformed phenotypic traits in colorectal cancer. Combining experiments and computational analysis, we show that the Na+/H+ exchanger NHE9 contributes to proton leak and causes luminal alkalinization, which induces resting [Ca2+], and in consequence, represses cAMP levels, creating a feedback loop that echoes nutrient deprivation or hypoxia. Higher NHE9 expression in cancer epithelia is associated with a hybrid epithelial-mesenchymal (E/M) state, poor prognosis, tumor budding, and invasive growth in vitro and in vivo. These findings point to NHE9-mediated cAMP suppression as a pseudostarvation-induced invasion state and potential therapeutic vulnerability in colorectal cancer. Our observations lay the groundwork for future research into the complexities of endosome-driven metabolic reprogramming and phenotype switching and the biology of cancer progression.Implications: Endosomal pH regulator NHE9 actively controls cytosolic Ca2+ levels to downregulate the adenylate cyclase-cAMP system, enabling colorectal cancer cells to acquire hybrid E/M characteristics and promoting metastatic progression.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139692465","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

Pediatric Chordoma: A Tale of Two Genomes 小儿脊索瘤两个基因组的故事

IF 5.2 2区医学

Molecular Cancer Research Pub Date : 2024-05-01 DOI: 10.1158/1541-7786.mcr-23-0741

Katrina O’Halloran, Hesamedin Hakimjavadi, Moiz Bootwalla, Dejerianne Ostrow, Rhea Kerawala, Jennifer A. Cotter, Venkata Yellapantula, Kristiyana Kaneva, Nitin R. Wadhwani, Amy Treece, Nicholas K. Foreman, Sanda Alexandrescu, Jose Velazquez Vega, Jaclyn A. Biegel, Xiaowu Gai

{"title":"Pediatric Chordoma: A Tale of Two Genomes","authors":"Katrina O’Halloran, Hesamedin Hakimjavadi, Moiz Bootwalla, Dejerianne Ostrow, Rhea Kerawala, Jennifer A. Cotter, Venkata Yellapantula, Kristiyana Kaneva, Nitin R. Wadhwani, Amy Treece, Nicholas K. Foreman, Sanda Alexandrescu, Jose Velazquez Vega, Jaclyn A. Biegel, Xiaowu Gai","doi":"10.1158/1541-7786.mcr-23-0741","DOIUrl":"https://doi.org/10.1158/1541-7786.mcr-23-0741","url":null,"abstract":"Little is known regarding the genomic alterations in chordoma, with the exception of loss of SMARCB1, a core member of the SWI/SNF complex, in poorly differentiated chordomas. A TBXT duplication and rs2305089 polymorphism, located at 6q27, are known genetic susceptibility loci. A comprehensive genomic analysis of the nuclear and mitochondrial genomes in pediatric chordoma has not yet been reported. In this study, we performed whole exome and mitochondrial DNA (mtDNA) genome sequencing on 29 chordomas from 23 pediatric patients. Findings were compared with that from whole genome sequencing datasets of 80 adult skull base chordoma patients. In the pediatric chordoma cohort, 81% percent of the somatic mtDNA mutations were observed in NADH complex genes, which is significantly enriched compared to the rest of the mtDNA genes (p=0.001). In adult chordomas, mtDNA mutations were also enriched in the NADH complex genes (p&lt;0.0001). Furthermore, a progressive increase in heteroplasmy of non-synonymous mtDNA mutations was noted in patients with multiple tumors (p=0.0007). In the nuclear genome, rare likely germline in-frame indels in ARID1B, a member of the SWI/SNF complex located at 6q25.3, were observed in five pediatric patients (22%) and four patients in the adult cohort (5%). The frequency of rare ARID1B indels in the pediatric cohort is significantly higher than that of the adult cohort (p=0.0236, Fisher’s exact test), but they were both significantly higher than that in the ethnicity-matched populations (p&lt;5.9e-07 and p&lt;0.0001174, respectively). Implications: germline ARID1B indels and mtDNA aberrations appear important for chordoma genesis, especially in pediatric chordoma.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140836896","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

NSCLC extracellular vesicles containing miR-374a-5p promote leptomeningeal metastasis by influencing blood‒brain barrier permeability 含有 miR-374a-5p 的 NSCLC 细胞外囊泡通过影响血脑屏障的通透性促进脑膜转移

IF 5.2 2区医学

Molecular Cancer Research Pub Date : 2024-04-19 DOI: 10.1158/1541-7786.mcr-24-0052

Jie Jin, Yumeng Cui, Huicong Niu, Yanli Lin, Xiaojie Wu, Xuejiao Qi, Kaixuan Bai, Yu Zhang, Youliang Wang, Hui Bu

{"title":"NSCLC extracellular vesicles containing miR-374a-5p promote leptomeningeal metastasis by influencing blood‒brain barrier permeability","authors":"Jie Jin, Yumeng Cui, Huicong Niu, Yanli Lin, Xiaojie Wu, Xuejiao Qi, Kaixuan Bai, Yu Zhang, Youliang Wang, Hui Bu","doi":"10.1158/1541-7786.mcr-24-0052","DOIUrl":"https://doi.org/10.1158/1541-7786.mcr-24-0052","url":null,"abstract":"Leptomeningeal metastasis (LM) is a devastating complication of advanced non-small cell lung cancer (NSCLC). Diagnosis and monitoring of LM can be challenging. Extracellular vesicles (EVs) microRNAs (miRNAs) have become a new noninvasive diagnostic biomarker. The purpose of this study was to examine the clinical value and role of EVs miRNAs in NSCLC-LM. According to next-generation sequencing (NGS), miRNAs with differential expression of EVs in serum of NSCLC patients with LM and non-LM were detected to find biological markers for the diagnosis of LM. Cellular and in vivo experiments were conducted to explore the pathogenesis of EVs miRNA promoting LM in NSCLC. In the present study, we first demonstrated the serum level of EV-associated miR-374a-5p in patients with LM of lung cancer was much higher than that in patients without LM and was correlated with the survival time of patients with LM. Further studies showed that EVs miR-374a-5p efficiently destroys tight junctions and the integrity of the cerebral microvascular endothelial cell barrier, resulting in increased blood-brain barrier (BBB) permeability. Mechanistically, miR-374a-5p regulates the distribution of ZO-1 and occludin in endothelial cells by targeting ADD3, increasing vascular permeability and promoting LM. Implications: These results suggest that serum NSCLC-derived EVs miR-374a-5p is involved in premetastatic niche formation by regulating the permeability of BBB to promote NSCLC-LM, and can be used as a blood biomarker for the diagnosis and prognosis of NSCLC-LM.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140626950","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

ETS1, a target gene of the EWSR1::FLI1 fusion oncoprotein, regulates the expression of the focal adhesion protein TENSIN3 EWSR1::FLI1融合肿瘤蛋白的靶基因ETS1调控局灶粘附蛋白TENSIN3的表达

IF 5.2 2区医学

Molecular Cancer Research Pub Date : 2024-04-08 DOI: 10.1158/1541-7786.mcr-23-1090

Vernon Justice Ebegboni, Tamara L. Jones, Tayvia Brownmiller, Patrick X. Zhao, Erica C. Pehrsson, Soumya Sundara Rajan, Natasha J. Caplen

{"title":"ETS1, a target gene of the EWSR1::FLI1 fusion oncoprotein, regulates the expression of the focal adhesion protein TENSIN3","authors":"Vernon Justice Ebegboni, Tamara L. Jones, Tayvia Brownmiller, Patrick X. Zhao, Erica C. Pehrsson, Soumya Sundara Rajan, Natasha J. Caplen","doi":"10.1158/1541-7786.mcr-23-1090","DOIUrl":"https://doi.org/10.1158/1541-7786.mcr-23-1090","url":null,"abstract":"The mechanistic basis for the metastasis of Ewing sarcomas remains poorly understood, as these tumors harbor few mutations beyond the chromosomal translocation that initiates the disease. Instead, the epigenome of Ewing sarcoma (EWS) cells reflects the regulatory state of genes associated with the DNA binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the EWSR1::FLI1/ERG’s repression of transcription factor genes, concentrating on those that exhibit a broader range of expression in tumors than in EWS cell lines. Focusing on one of these target genes, ETS1, we detected EWSR1::FLI1 binding and an H3K27me3 repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1’s binding of promoter regions, substantially altering the transcriptome of EWS cells, including the upregulation of the gene encoding TENSIN3 (TNS3), a focal adhesion protein. EWS cell lines expressing ETS1 (CRISPRa) exhibited increased TNS3 expression and enhanced movement compared to control cells. Visualization of control EWS cells showed a distributed vinculin signal and a network-like organization of F-actin; in contrast, ETS1-activated EWS cells showed an accumulation of vinculin and F-actin towards the plasma membrane. Interestingly, the phenotype of ETS1-activated EWS cell lines depleted of TNS3 resembled the phenotype of the control cells. Critically, these findings have clinical relevance as TNS3 expression in EWS tumors positively correlates with that of ETS1. Implications: ETS1’s transcriptional regulation of the gene encoding the focal adhesion protein TENSIN3 in Ewing sarcoma cells promotes cell movement, a critical step in the evolution of metastasis.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140564808","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