Molecular Cancer Research最新文献_第7页

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":" ","pages":"452-464"},"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":" ","pages":"495-507"},"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":" ","pages":"465-481"},"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":"50 1","pages":""},"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":"1 1","pages":""},"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":"193 1","pages":""},"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

Peritoneal Microenvironment Promotes Appendiceal Adenocarcinoma Growth: A Multi-omics Approach Using Patient-Derived Xenografts. 腹膜微环境促进阑尾腺癌生长：利用患者衍生异种移植的多组学方法。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-04-02 DOI: 10.1158/1541-7786.MCR-23-0749

Vinay K Pattalachinti, Ichiaki Ito, Saikat Chowdhury, Abdelrahman Yousef, Yue Gu, Betul Beyza Gunes, Emma R Salle, Melissa W Taggart, Keith Fournier, Natalie W Fowlkes, John Paul Shen

{"title":"Peritoneal Microenvironment Promotes Appendiceal Adenocarcinoma Growth: A Multi-omics Approach Using Patient-Derived Xenografts.","authors":"Vinay K Pattalachinti, Ichiaki Ito, Saikat Chowdhury, Abdelrahman Yousef, Yue Gu, Betul Beyza Gunes, Emma R Salle, Melissa W Taggart, Keith Fournier, Natalie W Fowlkes, John Paul Shen","doi":"10.1158/1541-7786.MCR-23-0749","DOIUrl":"10.1158/1541-7786.MCR-23-0749","url":null,"abstract":"Appendiceal adenocarcinoma (AA) is unique from other gastrointestinal malignancies in that it almost exclusively metastasizes to the peritoneal cavity. However, few studies have investigated the molecular interaction of the peritoneal microenvironment and AA. Here, we use a multi-omics approach with orthotopic and flank-implanted patient-derived xenografts (PDX) to study the effect of the peritoneal microenvironment on AA. AA tumors implanted in the peritoneal microenvironment tended to grow faster and displayed greater nuclear expression of Ki-67 relative to the same tumors implanted in the flank. Comparing the tumor-specific transcriptome (excluding stromal transcription), the peritoneal microenvironment relatively upregulated genes related to proliferation, including MKI67 and EXO1. Peritoneal tumors were also enriched for proliferative gene sets, including E2F and Myc Targets. Proteomic studies found a 2.5-fold increased ratio of active-to-inactive phosphoforms of the YAP oncoprotein in peritoneal tumors, indicating downregulation of Hippo signaling.Implications: The peritoneal microenvironment promotes growth of appendiceal tumors and expression of proliferative pathways in PDXs.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"329-336"},"PeriodicalIF":4.1,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10987270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472739","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

AIbZIP/CREB3L4 Promotes Cell Proliferation via the SKP2-p27 Axis in Luminal Androgen Receptor Subtype Triple-Negative Breast Cancer. AIbZIP/CREB3L4通过SKP2-p27轴促进腔隙性雄激素受体亚型三阴性乳腺癌的细胞增殖

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-04-02 DOI: 10.1158/1541-7786.MCR-23-0629

Taichi Ito, Atsushi Saito, Yasunao Kamikawa, Nayuta Nakazawa, Kazunori Imaizumi

{"title":"AIbZIP/CREB3L4 Promotes Cell Proliferation via the SKP2-p27 Axis in Luminal Androgen Receptor Subtype Triple-Negative Breast Cancer.","authors":"Taichi Ito, Atsushi Saito, Yasunao Kamikawa, Nayuta Nakazawa, Kazunori Imaizumi","doi":"10.1158/1541-7786.MCR-23-0629","DOIUrl":"10.1158/1541-7786.MCR-23-0629","url":null,"abstract":"Breast cancer ranks first in incidence and fifth in cancer-related deaths among all types of cancer globally. Among breast cancer, triple-negative breast cancer (TNBC) has few known therapeutic targets and a poor prognosis. Therefore, new therapeutic targets and strategies against TNBC are required. We found that androgen-induced basic leucine zipper (AIbZIP), also known as cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4), which is encoded by Creb3l4, is highly upregulated in a particular subtype of TNBC, luminal androgen receptor (LAR) subtype. We analyzed the function of AIbZIP through depletion of AIbZIP by siRNA knockdown in LAR subtype TNBC cell lines, MFM223 and MDAMB453. In AIbZIP-depleted cells, the proliferation ratios of cells were greatly suppressed. Moreover, G1-S transition was inhibited in AIbZIP-depleted cells. We comprehensively analyzed the expression levels of proteins that regulate G1-S transition and found that p27 was specifically upregulated in AIbZIP-depleted cells. Furthermore, we identified that this p27 downregulation was caused by protein degradation modulated by the ubiquitin-proteasome system via F-box protein S-phase kinase-associated protein 2 (SKP2) upregulation. Our findings demonstrate that AIbZIP is a novel p27-SKP2 pathway-regulating factor and a potential molecule that contributes to LAR subtype TNBC progression.Implications: This research shows a new mechanism for the proliferation of LAR subtype TNBC regulated by AIbZIP, that may provide novel insight into the LAR subtype TNBC progression and the molecular mechanisms involved in cell proliferation.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"373-385"},"PeriodicalIF":4.1,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10985479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139491345","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

NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth. NRAS 突变体决定了黑色素瘤肿瘤生长所需的 AHCYL1 控制的 ER 钙平衡。

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-04-02 DOI: 10.1158/1541-7786.MCR-23-0445

Chufan Cai, Jiayi Tu, Jeronimo Najarro, Rukang Zhang, Hao Fan, Freya Q Zhang, Jiacheng Li, Zhicheng Xie, Rui Su, Lei Dong, Nicole Arellano, Michele Ciboddo, Shannon E Elf, Xue Gao, Jing Chen, Rong Wu

{"title":"NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth.","authors":"Chufan Cai, Jiayi Tu, Jeronimo Najarro, Rukang Zhang, Hao Fan, Freya Q Zhang, Jiacheng Li, Zhicheng Xie, Rui Su, Lei Dong, Nicole Arellano, Michele Ciboddo, Shannon E Elf, Xue Gao, Jing Chen, Rong Wu","doi":"10.1158/1541-7786.MCR-23-0445","DOIUrl":"10.1158/1541-7786.MCR-23-0445","url":null,"abstract":"Calcium homeostasis is critical for cell proliferation, and emerging evidence shows that cancer cells exhibit altered calcium signals to fulfill their need for proliferation. However, it remains unclear whether there are oncogene-specific calcium homeostasis regulations that can expose novel therapeutic targets. Here, from RNAi screen, we report that adenosylhomocysteinase like protein 1 (AHCYL1), a suppressor of the endoplasmic reticulum (ER) calcium channel protein inositol trisphosphate receptor (IP3R), is selectively upregulated and critical for cell proliferation and tumor growth potential of human NRAS-mutated melanoma, but not for melanoma expressing BRAF V600E. Mechanistically, AHCYL1 deficiency results in decreased ER calcium levels, activates the unfolded protein response (UPR), and triggers downstream apoptosis. In addition, we show that AHCYL1 transcription is regulated by activating transcription factor 2 (ATF2) in NRAS-mutated melanoma. Our work provides evidence for oncogene-specific calcium regulations and suggests AHCYL1 as a novel therapeutic target for RAS mutant-expressing human cancers, including melanoma.Implications: Our findings suggest that targeting the AHCYL1-IP3R axis presents a novel therapeutic approach for NRAS-mutated melanomas, with potential applicability to all cancers harboring RAS mutations, such as KRAS-mutated human colorectal cancers.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"386-401"},"PeriodicalIF":4.1,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10987265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139642586","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

Semi-Supervised, Attention-Based Deep Learning for Predicting TMPRSS2:ERG Fusion Status in Prostate Cancer Using Whole Slide Images. 利用全切片图像预测前列腺癌 TMPRSS2:ERG 融合状态的半监督式、基于注意力的深度学习技术

IF 4.1 2区医学

Molecular Cancer Research Pub Date : 2024-04-02 DOI: 10.1158/1541-7786.MCR-23-0639

Mohamed Omar, Zhuoran Xu, Sophie B Rand, Mohammad K Alexanderani, Daniela C Salles, Itzel Valencia, Edward M Schaeffer, Brian D Robinson, Tamara L Lotan, Massimo Loda, Luigi Marchionni

引用次数: 0