Molecular Cancer Research最新文献

{"title":"LRRC75A-AS1 Drives the Epithelial-Mesenchymal Transition in Cervical Cancer by Binding IGF2BP1 and Inhibiting SYVN1-Mediated NLRP3 Ubiquitination.","authors":"Hongying Sui, Caixia Shi, Zhipeng Yan, Jinyang Chen, Lin Man, Fang Wang","doi":"10.1158/1541-7786.MCR-23-0478","DOIUrl":"10.1158/1541-7786.MCR-23-0478","url":null,"abstract":"<p><p>Cervical cancer severely affects women's health with increased incidence and poor survival for patients with metastasis. Our study aims to investigate the mechanism by which lncRNA LRRC75A-AS1 regulates the epithelial-mesenchymal transition (EMT) of cervical cancer through modulating m6A and ubiquitination modification. In this study, tumor tissues were collected from patients to analyze the expression of LRRC75A-AS1 and SYVN1. Migratory and invasive capacities of HeLa and CaSki cells were evaluated with wound healing and transwell assays. CCK-8 and EdU incor-poration assays were employed to examine cell proliferation. The interaction between LRRC75A-AS1, IGF2BP1, SYVN1, and NLRP3 was evaluated through RNA immunoprecipitation, RNA pull-down, FISH, and coimmunoprecipitation assays, respectively. MeRIP-qPCR was applied to analyze the m6A modification of SYVN1 mRNA. A subcutaneous tumor model of cervical cancer was established. We showed LRRC75A-AS1 was upregulated in tumor tissues, and LRRC75A-AS1 enhanced EMT through activating NLRP3/IL1β/Smad2/3 signaling in cervical cancer. Furthermore, LRRC75A-AS1 inhibited SYVN1-mediated NLRP3 ubiquitination by destabilizing SYVN1 mRNA. LRRC75A-AS1 competitively bound to IGF2BP1 protein and subsequently impaired the m6A modification of SYVN1 mRNA and its stability. Knockdown of LRRC75A-AS1 repressed EMT and tumor growth via inhibiting NLRP3/IL-1β/Smad2/3 signaling in mice. In conclusion, LRRC75A-AS1 competitively binds to IGF2BP1 protein to destabilize SYVN1 mRNA, subsequently suppresses SYVN1-mediated NLRP3 ubiquitination degradation and activates IL1β/Smad2/3 signaling, thus promoting EMT in cervical cancer. Implication: LRRC75A-AS1 promotes cervical cancer progression, and this study suggests LRRC75A-AS1 as a new therapeutic target for cervical cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1075-1087"},"PeriodicalIF":4.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098293","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}

{"title":"Ruthenium Drug BOLD-100 Regulates BRAFMT Colorectal Cancer Cell Apoptosis through AhR/ROS/ATR Signaling Axis Modulation.","authors":"Daryl Griffin, Robbie Carson, Debbie Moss, Tamas Sessler, Deborah Lavin, Vijay K Tiwari, Shivaali Karelia, Richard Kennedy, Kienan I Savage, Simon McDade, Adam Carie, Jim Pankovich, Mark Bazett, Sandra Van Schaeybroeck","doi":"10.1158/1541-7786.MCR-24-0151","DOIUrl":"10.1158/1541-7786.MCR-24-0151","url":null,"abstract":"<p><p>Patients with class I V600EBRAF-mutant (MT) colorectal cancer exhibit a poor prognosis, and their response to combined anti-BRAF/EGFR inhibition remains limited. An unmet need exits for further understanding the biology of V600EBRAFMT colorectal cancer. We used differential gene expression of BRAFWT and MT colorectal cancer cells to identify pathways underpinning BRAFMT colorectal cancer. We tested a panel of molecularly/genetically subtyped colorectal cancer cells for their sensitivity to the unfolded protein response (UPR) activator BOLD-100. To identify novel combination strategies for BOLD-100, we performed RNA sequencing and high-throughput drug screening. Pathway enrichment analysis identified significant enrichment of the UPR and DNA repair pathways in BRAFMT colorectal cancer. We found that oncogenic BRAF plays a crucial role in mediating the response to BOLD-100. Using a systems biology approach, we identified V600EBRAFMT-dependent activation of the replication stress response kinase ataxia telangiectasia and Rad3-related (ATR) as a key mediator of resistance to BOLD-100. Further analysis identified acute increases in BRAFMT-dependent-reactive oxygen species levels following treatment with BOLD-100, which promoted ATR/CHK1 activation and apoptosis. Furthermore, activation of reactive oxygen species/ATR/CHK1 following BOLD-100 was mediated through the AhR transcription factor and CYP1A1. Importantly, pharmacological blockade of this resistance pathway with ATR inhibitors synergistically increased BOLD-100-induced apoptosis and growth inhibition in BRAFMT models. These results highlight a possible novel therapeutic opportunity for BRAFMT colorectal cancer. Implications: BOLD-100 induces BRAFMT-dependent replication stress, and targeted strategies against replication stress (e.g., by using ATR inhibitors) in combination with BOLD-100 may serve as a potential novel therapeutic strategy for clinically aggressive BRAFMT colorectal cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1088-1101"},"PeriodicalIF":4.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856110","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}

{"title":"EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell-Dependent Manner.","authors":"Lily L Nguyen, Zachary L Watson, Raquel Ortega, Elizabeth R Woodruff, Kimberly R Jordan, Ritsuko Iwanaga, Tomomi M Yamamoto, Courtney A Bailey, Francis To, Shujian Lin, Fabian R Villagomez, Abigail D Jeong, Saketh R Guntupalli, Kian Behbakht, Veronica Gibaja, Nausica Arnoult, Edward B Chuong, Benjamin G Bitler","doi":"10.1158/1541-7786.MCR-24-0067","DOIUrl":"10.1158/1541-7786.MCR-24-0067","url":null,"abstract":"<p><p>Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising, and there is currently an unmet need to combat PARPi-resistant tumors. Here, we created an immunocompetent, PARPi-resistant mouse model to test the efficacy of combinatory PARPi and euchromatic histone methyltransferase 1/2 inhibitor (EHMTi) in the treatment of PARPi-resistant ovarian cancer. We discovered that inhibition of EHMT1/2 resensitizes cells to PARPi. Markedly, we show that single EHMTi and combinatory EHMTi/PARPi significantly reduced PARPi-resistant tumor burden and that this reduction is partially dependent on CD8 T cells. Altogether, our results show a low-toxicity drug that effectively treats PARPi-resistant ovarian cancer in an immune-dependent manner, supporting its entry into clinical development and potential incorporation of immunotherapy. Implications: Targeting the epigenome of therapy-resistant ovarian cancer induces an antitumor response mediated in part through an antitumor immune response.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1117-1127"},"PeriodicalIF":4.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11614706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971525","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}

{"title":"Defining Splicing Factor Requirements for Androgen Receptor Variant Synthesis in Advanced Prostate Cancer.","authors":"Laura Walker, Ruaridh Duncan, Beth Adamson, Hannah Kendall, Nicholas Brittain, Sara Luzzi, Dominic Jones, Lewis Chaytor, Samantha Peel, Claire Crafter, Daniel J O'Neill, Luke Gaughan","doi":"10.1158/1541-7786.MCR-23-0958","DOIUrl":"10.1158/1541-7786.MCR-23-0958","url":null,"abstract":"<p><p>Resistance to androgen receptor (AR)-targeted therapies represents a major challenge in prostate cancer. A key mechanism of treatment resistance in patients who progress to castration-resistant prostate cancer (CRPC) is the generation of alternatively spliced AR variants (AR-V). Unlike full-length AR isoforms, AR-Vs are constitutively active and refractory to current receptor-targeting agents and hence drive tumor progression. Identifying regulators of AR-V synthesis may therefore provide new therapeutic opportunities in combination with conventional AR-targeting agents. Our understanding of AR transcript splicing, and the factors that control the synthesis of AR-Vs, remains limited. Although candidate-based approaches have identified a small number of AR-V splicing regulators, an unbiased analysis of splicing factors important for AR-V generation is required to fill an important knowledge gap and furnish the field with novel and tractable targets for prostate cancer treatment. To that end, we conducted a bespoke CRISPR screen to profile splicing factor requirements for AR-V synthesis. MFAP1 and CWC22 were shown to be required for the generation of AR-V mRNA transcripts, and their depletion resulted in reduced AR-V protein abundance and cell proliferation in several CRPC models. Global transcriptomic analysis of MFAP1-depleted cells revealed both AR-dependent and -independent transcriptional impacts, including genes associated with DNA damage response. As such, MFAP1 downregulation sensitized prostate cancer cells to ionizing radiation, suggesting that therapeutically targeting AR-V splicing could provide novel cellular vulnerabilities which can be exploited in CRPC. Implications: We have utilized a CRISPR screening approach to identify key regulators of pathogenic AR splicing in prostate cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1128-1142"},"PeriodicalIF":4.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350767","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}

{"title":"TEAD2 Promotes Hepatocellular Carcinoma Development and Sorafenib Resistance via TAK1 Transcriptional Activation.","authors":"Yahui Zhang, Yidan Ren, Guoying Dong, Qinlian Jiao, Nan Guo, Ping Gao, Ya Li, Yunshan Wang, Wei Zhao","doi":"10.1158/1541-7786.MCR-24-0060","DOIUrl":"10.1158/1541-7786.MCR-24-0060","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer, yet the effectiveness of treatment for patients with HCC is significantly hindered by the development of drug resistance to sorafenib. Through the application of accessibility sequencing to examine drug-resistant HCC tissues, we identified substantial alterations in chromatin accessibility in sorafenib-resistant patient-derived xenograft models. Employing multiomics data integration analysis, we confirmed that the key transcription factor TEAD2, which plays an important role in the Hippo signaling pathway, is a key factor in regulating sorafenib resistance in HCC. Functional assays illustrated that TEAD2 plays a role in promoting HCC progression and enhancing resistance to sorafenib. Mechanistically, we demonstrated that TEAD2 binds to the TAK1 promoter to modulate its expression. Furthermore, we established the involvement of TAK1 in mediating TEAD2-induced sorafenib resistance in HCC, a finding supported by the effectiveness of TAK1 inhibitors. Our research highlights that targeting the TEAD2-TAK1 axis can effectively mitigate drug resistance in patients with HCC receiving sorafenib treatment, offering a novel approach for enhancing the treatment outcomes and prognosis of individuals with HCC. Implications: Targeting the TEAD2-TAK1 axis presents a promising therapeutic strategy to overcome sorafenib resistance in HCC, potentially improving treatment outcomes and prognosis for patients.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1102-1116"},"PeriodicalIF":4.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897896","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}

{"title":"Retraction: miRNA-302b Suppresses Human Hepatocellular Carcinoma by Targeting AKT2.","authors":"Lumin Wang, Jiayi Yao, Xiaogang Zhang, Bo Guo, Xiaofeng Le, Mark Cubberly, Zongfang Li, Kejun Nan, Tusheng Song, Chen Huang","doi":"10.1158/1541-7786.MCR-24-0723","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0723","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"22 11","pages":"1067"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558318","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}

{"title":"Retraction: Role of Rac1 Pathway in Epithelial-to-Mesenchymal Transition and Cancer Stem-like Cell Phenotypes in Gastric Adenocarcinoma.","authors":"Changhwan Yoon, Seo-Jeong Cho, Kevin K Chang, Do Joong Park, Sandra W Ryeom, Sam S Yoon","doi":"10.1158/1541-7786.MCR-24-0857","DOIUrl":"10.1158/1541-7786.MCR-24-0857","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"22 11","pages":"1068"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558319","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}

{"title":"Retraction: CDX1 Expression Induced by CagA-Expressing Helicobacter pylori Promotes Gastric Tumorigenesis.","authors":"Sang Il Choi, Changhwan Yoon, Mi Ree Park, DaHyung Lee, Myeong-Cherl Kook, Jian-Xian Lin, Jun Hyuk Kang, Hassan Ashktorab, Duane T Smoot, Sam S Yoon, Soo-Jeong Cho","doi":"10.1158/1541-7786.MCR-24-0859","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0859","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"22 11","pages":"1065"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558316","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}

{"title":"GRAIL1 Stabilizes Misfolded Mutant p53 through a Ubiquitin Ligase-Independent, Chaperone Regulatory Function.","authors":"Paramita Ray, Sangeeta Jaiswal, Daysha Ferrer-Torres, Zhuwen Wang, Derek Nancarrow, Meghan Curtin, May San Martinho, Shannon M Lacy, Srimathi Kasturirangan, Dafydd Thomas, Jason R Spence, Matthias C Truttmann, Kiran H Lagisetty, Theodore S Lawrence, Thomas D Wang, David G Beer, Dipankar Ray","doi":"10.1158/1541-7786.MCR-24-0361","DOIUrl":"10.1158/1541-7786.MCR-24-0361","url":null,"abstract":"<p><p>Frequent (>70%) TP53 mutations often promote its protein stabilization, driving esophageal adenocarcinoma (EAC) development linked to poor survival and therapy resistance. We previously reported that during Barrett's esophagus progression to EAC, an isoform switch occurs in the E3 ubiquitin ligase RNF128 (aka GRAIL-gene related to anergy in lymphocytes), enriching isoform 1 (hereby GRAIL1) and stabilizing the mutant p53 protein. Consequently, GRAIL1 knockdown degrades mutant p53. But, how GRAIL1 stabilizes the mutant p53 protein remains unclear. In search for a mechanism, here, we performed biochemical and cell biology studies to identify that GRAIL has a binding domain (315-PMCKCDILKA-325) for heat shock protein 40/DNAJ. This interaction can influence DNAJ chaperone activity to modulate misfolded mutant p53 stability. As predicted, either the overexpression of a GRAIL fragment (Frag-J) encompassing the DNAJ binding domain or a cell-permeable peptide (Pep-J) encoding the above 10 amino acids can bind and inhibit DNAJ-Hsp70 co-chaperone activity, thus degrading misfolded mutant p53. Consequently, either Frag-J or Pep-J can reduce the survival of mutant p53 containing dysplastic Barrett's esophagus and EAC cells and inhibit the growth of patient-derived organoids of dysplastic Barrett's esophagus in 3D cultures. The misfolded mutant p53 targeting and growth inhibitory effects of Pep-J are comparable with simvastatin, a cholesterol-lowering drug that can degrade misfolded mutant p53 also via inhibiting DNAJA1, although by a distinct mechanism. Implications: We identified a novel ubiquitin ligase-independent, chaperone-regulating domain in GRAIL and further synthesized a first-in-class novel misfolded mutant p53 degrading peptide having future translational potential.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"996-1010"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634059","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}

{"title":"Editor's Note: Therapeutic Targeting of Nuclear γ-Tubulin in RB1-Negative Tumors.","authors":"Lisa Lindström, Bruno O Villoutreix, Sophie Lehn, Rebecka Hellsten, Elise Nilsson, Enisa Crneta, Roger Olsson, Maria Alvarado-Kristensson","doi":"10.1158/1541-7786.MCR-24-0792","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0792","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"22 11","pages":"1064"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558314","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}