Cancer gene therapy最新文献

{"title":"FBXO22 promotes HCC angiogenesis and metastasis via RPS5/AKT/HIF-1α/VEGF-A signaling axis","authors":"Zhen Lei, Yiming Luo, Junli Lu, Qinggang Fu, Chao Wang, Qian Chen, Zhiwei Zhang, Long Zhang","doi":"10.1038/s41417-024-00861-w","DOIUrl":"10.1038/s41417-024-00861-w","url":null,"abstract":"The gene F-box only protein 22 (FBXO22) has been discovered to promote the development of liver cancer tumors. Nevertheless, there remains considerable ambiguity regarding the involvement of FBXO22 in the processes of angiogenesis and metastasis in hepatocellular carcinoma (HCC). Our study has confirmed a significant upregulation of FBXO22 expression in both HCC samples and cellular models. The increased level of FBXO22 correlates strongly with the number of tumors, presence of vascular invasion, and poor prognosis. Experimental investigations have shown that FBXO22 significantly enhances angiogenesis and metastasis of HCC both in vitro and in vivo. Mechanistically, FBXO22 interacts with and ubiquitinates 40S ribosomal protein S5 (RPS5) on Lys85, thereby promoting its K48-linked ubiquitin-mediated degradation in the cytoplasm. Following a decrease in the expression of RPS5, activation of downstream PI3K/AKT signaling pathway occurs, leading to elevated levels of HIF-1α and vascular endothelial growth factor A (VEGF-A). Our study has shown that FBXO22 facilitates HCC angiogenesis and metastasis via the RPS5/AKT/HIF-1α/VEGF-A signaling axis. Notably, inhibition of FBXO22 enhances the efficacy of Lenvatinib both in vitro and in vivo. Therefore, FBXO22 may present itself as a potential target for therapeutic intervention in the treatment of HCC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"198-213"},"PeriodicalIF":4.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00861-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring metabolic reprogramming in esophageal cancer: the role of key enzymes in glucose, amino acid, and nucleotide pathways and targeted therapies","authors":"Xue-Man Dong, Lin Chen, Yu-Xin Xu, Pu Wu, Tian Xie, Zhao-Qian Liu","doi":"10.1038/s41417-024-00858-5","DOIUrl":"10.1038/s41417-024-00858-5","url":null,"abstract":"Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"165-183"},"PeriodicalIF":4.8,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00858-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Has_circ_ASH1L acts as a sponge for miR-1254 to promote the malignant progression of cervical cancer by targeting CD36","authors":"Jun Zhang, Yan Zhang, Xing Li, Yindi Bao, Jing Yang","doi":"10.1038/s41417-024-00866-5","DOIUrl":"10.1038/s41417-024-00866-5","url":null,"abstract":"Cervical cancer (CC) is a prevalent gynecological malignancy. Increasing evidence suggests that circular RNAs (circRNAs) play a pivotal role in the pathogenesis of CC. However, the regulatory function of circ_ASH1L in CC remains elusive. In this study, we aim to elucidate the precise role and underlying mechanism of circ_ASH1L in the malignant progression of CC. The human CC dataset GSE102686 was extracted from the Gene Expression Omnibus (GEO) database for the analysis of differentially expressed circRNAs. Target gene prediction softwares were utilized to predict the binding of miRNAs to circ_ASH1L sponge. The expression level of circ_ASH1L in CC tissues and cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The characteristics of circ_ASH1L were determined by RNase R digestion, actinomycin D, and nucleo-plasmic separation assays. The effects of circ_ASH1L, miR-1254, and CD36 gain-and-loss on the malignant progression of CC were investigated using Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, wound scratch, transwell, and Western blot assay. The effect of circ_ASH1L on tumorigenicity of CC cells in vivo was evaluated in nude mice through tumor xenograft assay. The targeted regulatory relationship between circ_ASH1L/miR-1254 as well as miR-1254/CD36 was validated by dual-luciferase reporter assay. We screened the differentially expressed circ_ASH1L from the GEO dataset GSE102686 and confirmed its circular structure. Furthermore, we observed a significant upregulation of circ_ASH1L in both CC tissues and cells. Overexpression of circ_ASH1L promotes proliferation, invasion, and migration of CC cells while inhibiting cell apoptosis. However, silencing circ_ASH1L showed opposite results and inhibited tumorigenicity of CC cells in nude mice. Furthermore, we have identified circ_ASH1L as a miR-1254 sponge in CC cells. Notably, our in vitro experiments demonstrated that exogenously modulating the expression of miR-1254 effectively counteracted the impact of circ_ASH1L on the malignant phenotypic characteristics of CC cells. Similarly, modulation of CD36 expression efficiently counteracted the effect of miR-1254 on the malignant biological behavior of CC cells. In conclusion, circ_ASH1L promoted the malignant progression of CC via upregulating CD36 expression through sponging miR-1254.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"214-226"},"PeriodicalIF":4.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PIK3CA mutation fortifies molecular determinants for immune signaling in vascular cancers","authors":"Donghee Lee, Emma C. Kozurek, Md Abdullah, Ethan J. Wong, Rong Li, Zhiyan Silvia Liu, Hai Dang Nguyen, Erin B. Dickerson, Jong Hyuk Kim","doi":"10.1038/s41417-024-00867-4","DOIUrl":"10.1038/s41417-024-00867-4","url":null,"abstract":"Angiosarcomas are a group of vascular cancers that form malignant blood vessels. These malignancies are seemingly inflamed primarily due to their pathognomonic nature, which consists of irregular endothelium and tortuous blood channels. PIK3CA mutations are oncogenic and disrupt the PI3K pathway. In this study, we aimed to define the molecular and functional consequences of oncogenic PIK3CA mutations in angiosarcoma. We first generated two isogenic hemangiosarcoma cell lines harboring the H1047R hotspot mutations in PIK3CA gene using CRISPR/Cas9. We found PIK3CA-mutant cells established distinct molecular signatures in global gene expression and chromatin accessibility, which were associated with enrichment of immune cytokine signaling, including IL-6, IL-8, and MCP-1. These molecular processes were disrupted by the PI3K-α specific inhibitor, alpelisib. We also observed that the molecular distinctions in PIK3CA-mutant cells were linked to metabolic reprogramming in glycolytic activity and mitochondrial respiration. Our multi-omics analysis revealed that activating PIK3CA mutations regulate molecular machinery that contributes to phenotypic alterations and resistance to alpelisib. Furthermore, we identified potential therapeutic vulnerabilities of PIK3CA mutations in response to PI3K-α inhibition mediated by MAPK signaling. In summary, we demonstrate that PIK3CA mutations perpetuate PI3K activation and reinforce immune enrichment to promote drug resistance in vascular cancers.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"254-267"},"PeriodicalIF":4.8,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00867-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Circular RNA hsa_circ_0009172 suppresses gastric cancer by regulation of microRNA-485-3p-mediated NTRK3","authors":"Hao Wang, Nan Wang, Xiaoli Zheng, Lei Wu, Chengcheng Fan, Xue Li, Ke Ye, Suxia Han","doi":"10.1038/s41417-024-00870-9","DOIUrl":"10.1038/s41417-024-00870-9","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 1","pages":"148-148"},"PeriodicalIF":4.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00870-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ITGA3 promotes pancreatic cancer progression through HIF1α- and c-Myc-driven glycolysis in a collagen I-dependent autocrine manner","authors":"Rongkun Li, Qian Ji, Shengqiao Fu, Jichun Gu, Dejun Liu, Lu Wang, Xiao Yuan, Yi Wen, Chunhua Dai, Hengchao Li","doi":"10.1038/s41417-024-00864-7","DOIUrl":"10.1038/s41417-024-00864-7","url":null,"abstract":"Pancreatic cancer is characterized by severe metabolic stress due to its prominent desmoplasia and poor vascularization. Integrin subunit alpha 3 (ITGA3) is a cell surface adhesion protein involved in tumor progression. However, the role of ITGA3 in pancreatic cancer progression, especially in metabolic reprogramming, remains largely unknown. In this study, we found that ITGA3 expression is elevated in pancreatic cancer tissues and predicts poor prognosis for patients with pancreatic cancer. Functional assays revealed that ITGA3 promotes the growth and liver metastasis of pancreatic cancer via boosting glycolysis. Mechanistically, Collagen I (Col1) derived from cancer cells acts as a ligand for ITGA3 to activate the FAK/PI3K/AKT/mTOR signaling pathway in an autocrine manner, thereby increasing the expression of HIF1α and c-Myc, two critical regulators of glycolysis. Blockade of Col1 by siRNA or of ITGA3 by a blocking antibody leads to specific inactivation of the FAK/PI3K/AKT/mTOR pathway and impairs malignant tumor behaviors induced by ITGA3. Thus, our data indicate that ITGA3 enhances glycolysis to promote pancreatic cancer growth and metastasis via increasing HIF1α and c-Myc expression in a Col1-dependent autocrine manner, making ITGA3 as a candidate diagnostic biomarker and a potential therapeutic target for pancreatic cancer.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"240-253"},"PeriodicalIF":4.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRP11-AS1 mediates enterotoxigenic Bacteroides fragilis-related carcinogenesis in colorectal Cancer via the miR-149-3p/CDK4 pathway","authors":"Zhongguang Wu, Mengqiu Yu, Yu Zeng, Yingfeng Huang, Weidong Zheng","doi":"10.1038/s41417-024-00862-9","DOIUrl":"10.1038/s41417-024-00862-9","url":null,"abstract":"Long noncoding RNAs (lncRNAs) are critical in tumorigenesis and show potential for tumor diagnosis and therapy. Enterotoxigenic Bacteroides fragilis (ETBF), known for producing enterotoxins, is implicated in human gut tumorigenesis, yet the underlying mechanisms are not fully elucidated. This study aims to clarify the molecular mechanisms by which lncRNAs contribute to ETBF-induced tumorigenesis, with a focus on LRP11-AS1’s role in modulating ETBF’s colorectal carcinogenesis. We found a marked increase in LRP11-AS1 expression in colorectal cancer (CRC) tissues compared to adjacent non-tumorous tissues. In vitro, CRC cells exposed to ETBF showed elevated LRP11-AS1 levels. Mechanistically, LRP11-AS1 was shown to enhance CDK4 expression by competitively binding to miR-149-3p. These results indicate that LRP11-AS1 may facilitate ETBF-related carcinogenesis in CRC and could serve as a therapeutic target and diagnostic biomarker for ETBF-associated CRC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 2","pages":"184-197"},"PeriodicalIF":4.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00862-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The deubiquitinating enzyme ATXN3 promotes hepatocellular carcinoma progression by stabilizing TAZ","authors":"Yuanhao Peng, Hui Nie, Kuo Kang, Xuanxuan Li, Yongguang Tao, Yangying Zhou","doi":"10.1038/s41417-024-00869-2","DOIUrl":"10.1038/s41417-024-00869-2","url":null,"abstract":"Hepatocellular carcinoma (HCC) was a primary cause of cancer-related morbidity and mortality in China. ATXN3 was a deubiquitinase (DUB) associated with spinocerebellar ataxia, widely expressed in the cytoplasm and nucleus of cells in the central nervous system and other tissues. The crucial role of the Hippo pathway in tumorigenesis has been established, among which TAZ served as one of the key molecules. However, the mechanisms underlying the deubiquitinase and TAZ in HCC remained largely unknown. In the present study, we explored that ATXN3 was overexpressed in HCC. ATXN3 promoted the proliferation, migration, invasion, and tumorigenic ability of HCC in vitro and in vivo. Besides, we explored that ATXN3 was positively associated with TAZ in HCC. ATXN3 could interact with, stabilize, and deubiquitylate TAZ in a deubiquitylase-dependent manner. Specifically, this interaction was primarily mediated by the C-terminal domain of TAZ and Josephin domain of ATXN3, thereby inhibiting the K48-linked ubiquitin chain on TAZ. Furthermore, we demonstrated that ATXN3 promoted the occurrence and development of HCC by regulating TAZ. Therefore, our study revealed the oncogenic function of ATXN3 and an interesting deubiquitination mechanism of ATXN3 and TAZ in HCC, providing new insights into the diagnosis and treatment of HCC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 1","pages":"136-145"},"PeriodicalIF":4.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N6-methyladenosine modification of RIMS binding protein 2 promotes head and neck squamous cell carcinoma proliferation and radiotherapy tolerance through endoplasmic reticulum stress","authors":"Xinyu Sun, Yanshu Zhang, Huirong Wang, Xi Pu, Xiao Yuan, Yuntong Liang, Hao Liu, Xu Wang, Hanqiang Lu","doi":"10.1038/s41417-024-00863-8","DOIUrl":"10.1038/s41417-024-00863-8","url":null,"abstract":"Insulin-like growth factor binding protein 2 (IGF2BP2) fulfills a key role in the development of head and neck squamous cell carcinoma (HNSCC). Radiotherapy is an effective method to treat HNSCC; however, radiation resistance is the main reason for treatment failure. At present, the carcinogenic role of IGF2BP2 in terms of the proliferation of HNSCC and the radioresistance of its therapy remain poorly understood. In the present study, patients with HNSCC with higher IGF2BP2 expression levels were associated with shorter survival times. IGF2BP2 is significantly upregulated in HNSCC cells compared with irradiated cell. Based on functional studies, IGF2BP2 was found to promote HNSCC cell proliferation and tolerance to radiotherapy both in vitro and in vivo. In terms of the underlying mechanism, RIMS binding protein 2 (RIMBP2) was found to be highly expressed in HNSCC and to promote the proliferation of HNSCC and radiotherapy resistance. RIMBP2 was shown to be a direct target of IGF2BP2, activating endoplasmic reticulum stress in HNSCC. In addition, it has been demonstrated that IGF2BP2, as m6A reader, is able to promote RIMBP2 stability via binding to m6A sites in the RIMBP2-coding sequence region. Therefore, the present study has unveiled a potential mechanism via which IGF2BP2 promotes HNSCC development and radiotherapy resistance; moreover, from a therapeutic perspective, IGF2BP2 may serve as a potential therapeutic target and a valuable prognostic biomarker for patients with HNSCC who have developed tolerance towards radiotherapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 1","pages":"122-135"},"PeriodicalIF":4.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Expression of Concern: E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells","authors":"Xiao-Mei Rao, Michael T. Tseng, Xinyu Zheng, Yanbin Dong, Azemat Jamshidi-Parsian, Timothy C. Thompson, Malcolm K. Brenner, Kelly M. McMasters, Heshan Sam Zhou","doi":"10.1038/s41417-024-00860-x","DOIUrl":"10.1038/s41417-024-00860-x","url":null,"abstract":"","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 1","pages":"147-147"},"PeriodicalIF":4.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41417-024-00860-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}