Molecular Cancer Research最新文献

{"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":"Tumor-derived EBV-miR-BART2-5p promotes nasopharyngeal carcinoma metastasis by inducing pre-metastatic endothelial cell pyroptosis.","authors":"Xingrui Chen, Qiqi Li, Xiaoyan Fu, Jike Li, Jun Deng, Qianbing Zhang, Mengying Qiu, Xiaoming Lyu, Linbo Cai, Hainan Li, Xin Li, Kaitai Yao, Jiahong Wang, Zhongxi Huang, Liang Chen, Jiangyu Zhang, Dengke Li","doi":"10.1158/1541-7786.MCR-24-0165","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0165","url":null,"abstract":"<p><p>Extravasation is a key step in tumor metastasis. Epstein‒Barr virus (EBV) plays a crucial role in nasopharyngeal carcinoma (NPC) metastasis. However, the functions and molecular mechanisms of EBV during tumor cell extravasation remains unclear. Here, we showed that the expression of pyroptosis-associated proteins is greater in the endothelial cells of metastatic NPC tissues than in those of nontumor tissues Exosomes derived from NPC cells promoted endothelial cell pyroptosis, vascular permeability, and tumor cell extravasation. Moreover, we found that BART2-5p is abundant in serum exosomes from NPC patients with metastasis and NPC cells, and that it regulates endothelial cell pyroptosis in pre-metastatic organs via MRE11A. Exosomes containing a BART2-5p inhibitor and AAV-MRE11A attenuated endothelial cell pyroptosis and tumor metastasis. Moreover, in the endothelial cells of metastatic tissues from NPC patients, the BART2-5p level was positively associated with pyroptosis-related protein expression. Collectively, our findings suggest that exosomal BART2-5p is involved in pre-metastatic niche formation, identifying secreted BART2-5p as a potential therapeutic target for NPC metastasis. Implications: The finding that secreted BART2-5p is involved in pre-metastatic niche formation may aid the development of potential therapeutic target for NPC metastasis.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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}

{"title":"Expanding Our Horizon to Inform Cutting Edge Mechanistic Studies: Cancer Research Resources.","authors":"Massimo Loda","doi":"10.1158/1541-7786.MCR-24-0884","DOIUrl":"10.1158/1541-7786.MCR-24-0884","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"22 11","pages":"995"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558315","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":"METTL14-Mediated Bim mRNA m6A Modification Augments Osimertinib Sensitivity in EGFR-Mutant NSCLC Cells.","authors":"Siwen Fan, Xinwu Lv, Chuantao Zhang, Bingbing Zeng, Yanqing Liang, Danyang Chen, Zumin Xu, Pan Li, Shanshan Wu, Hao Liu, Kai Luo, Zongcai Liu, Yanmei Yi","doi":"10.1158/1541-7786.MCR-23-1018","DOIUrl":"10.1158/1541-7786.MCR-23-1018","url":null,"abstract":"<p><p>Resistance to osimertinib represents a significant challenge for the successful treatment of non-small cell lung cancer (NSCLC) harboring activating mutations in EGFR. N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates osimertinib resistance of NSCLC remains unknown. In this study, we demonstrated that developing osimertinib-resistant phenotypes depends on m6A reduction resulting from downexpression of m6A methyltransferase METTL14 in EGFR-mutant NSCLCs. Both in vitro and in vivo assays showed that specific knockdown of METTL14 was sufficient to confer osimertinib resistance and that elevated expression of METTL14 rescued the efficacy of osimertinib in the resistant NSCLC cells. Mechanistically, METTL14 promoted m6A methylation of pro-apoptotic Bim mRNA and increased Bim mRNA stability and expression, resulting in activating the Bim-dependent pro-apoptotic signaling and thereby promoting osimertinib-induced cell apoptosis. Analysis of clinical samples revealed that decreased expression of METTL14 was observed in osimertinib-resistant NSCLC tissues and significantly associated with a poor prognosis. In conclusion, our study reveals a novel regulatory mechanism by which METTL14-mediated m6A methylation of Bim mRNA inhibited osimertinib resistance of NSCLC cells. It offers more evidences for the involvement of m6A modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors. Implications: This study offers more evidences for the involvement of METTL14-mediated N6-methyladenosine modification in regulation of osimertinib resistance and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR tyrosine kinase inhibitors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1051-1063"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492786","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: KRAS Activation in Gastric Adenocarcinoma Stimulates Epithelial-to-Mesenchymal Transition to Cancer Stem-Like Cells and Promotes Metastasis.","authors":"Changhwan Yoon, Jacob Till, Soo-Jeong Cho, Kevin K Chang, Jian-Xian Lin, Chang-Ming Huang, Sandra Ryeom, Sam S Yoon","doi":"10.1158/1541-7786.MCR-24-0858","DOIUrl":"10.1158/1541-7786.MCR-24-0858","url":null,"abstract":"","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"22 11","pages":"1066"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558317","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}