Pub Date : 2024-06-17DOI: 10.1016/j.gendis.2024.101353
Muyuan Ma, Jianhong An, Tingting Jiang, Keping Xie
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterized by insidious onset and lack of effective therapy. The molecular pathogenesis of PDA remains to be understood fully. Transcriptional factor GATA6 is an important transcriptional regulator in normal pancreas development, particularly in the initial specification and differentiation of the pancreas. Recent studies have linked pancreatic malignancy closely to GATA6. Increased levels of GATA6 expression enhance pancreatic cancer cell growth. GATA6 emerges as a lineage-specific oncogenic factor in PDA, augmenting the oncogenic phenotypes of PDA cells upon its overexpression. However, elevated GATA6 levels are correlated with well-differentiated tumors and a more favorable patient prognosis. Experimental evidence in genetic mouse models has revealed a tumor-suppressive role for GATA6. The circumstantial roles of GATA6 in pancreatic tumorigenesis remain to be defined. This review aims to elucidate recent advances in comprehending GATA6, emphasizing its crucial roles in both pancreas physiology and pathology. Special attention will be given to its involvement in PDA pathogenesis, exploring its potential as a novel biomarker and a promising therapeutic target for PDA.
{"title":"GATA6 in pancreatic cancer initiation and progression","authors":"Muyuan Ma, Jianhong An, Tingting Jiang, Keping Xie","doi":"10.1016/j.gendis.2024.101353","DOIUrl":"https://doi.org/10.1016/j.gendis.2024.101353","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterized by insidious onset and lack of effective therapy. The molecular pathogenesis of PDA remains to be understood fully. Transcriptional factor GATA6 is an important transcriptional regulator in normal pancreas development, particularly in the initial specification and differentiation of the pancreas. Recent studies have linked pancreatic malignancy closely to GATA6. Increased levels of GATA6 expression enhance pancreatic cancer cell growth. GATA6 emerges as a lineage-specific oncogenic factor in PDA, augmenting the oncogenic phenotypes of PDA cells upon its overexpression. However, elevated GATA6 levels are correlated with well-differentiated tumors and a more favorable patient prognosis. Experimental evidence in genetic mouse models has revealed a tumor-suppressive role for GATA6. The circumstantial roles of GATA6 in pancreatic tumorigenesis remain to be defined. This review aims to elucidate recent advances in comprehending GATA6, emphasizing its crucial roles in both pancreas physiology and pathology. Special attention will be given to its involvement in PDA pathogenesis, exploring its potential as a novel biomarker and a promising therapeutic target for PDA.","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141547899","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}
Pub Date : 2024-06-17DOI: 10.1016/j.gendis.2024.101354
Omkar Desai, Moeez Rathore, Christina S. Boutros, Michel'le Wright, Elizabeth Bryson, Kimberly Curry, Rui Wang
HER3, formally referred to as ERB-B2 receptor tyrosine kinase 3, is a member of the ErbB receptor tyrosine kinases (also known as EGFR) family. HER3 plays a significant pro-cancer role in various types of cancer due to its overexpression and abnormal activation, which initiates downstream signaling pathways crucial in cancer cell survival and progression. As a result, numerous monoclonal antibodies have been developed to block HER3 activation and subsequent signaling pathways. While pre-clinical investigations have effectively showcased significant anti-cancer effects of HER3-targeted therapies, these therapies have had little impact on cancer patient outcomes in the clinic, except for patients with rare fusion mutations. This review offers a comprehensive description of the oncogenic functions of HER3, encompassing its structure and mediating signaling pathways. More importantly, it provides an in-depth exploration of past and ongoing clinical trials investigating HER3-targeted therapies for distinct types of cancer and discusses the tumor microenvironment and other critical determinants that may contribute to the observed suboptimal outcomes in most clinical studies using HER3-targeted therapies. Lastly, we suggest alternative approaches and the exploration of novel strategies to potentially improve the efficacy of targeting the pivotal oncogenic HER3 signaling pathway in future translational investigations.
{"title":"HER3: Unmasking a twist in the tale of a previously unsuccessful therapeutic pursuit targeting a key cancer survival pathway","authors":"Omkar Desai, Moeez Rathore, Christina S. Boutros, Michel'le Wright, Elizabeth Bryson, Kimberly Curry, Rui Wang","doi":"10.1016/j.gendis.2024.101354","DOIUrl":"https://doi.org/10.1016/j.gendis.2024.101354","url":null,"abstract":"HER3, formally referred to as ERB-B2 receptor tyrosine kinase 3, is a member of the ErbB receptor tyrosine kinases (also known as EGFR) family. HER3 plays a significant pro-cancer role in various types of cancer due to its overexpression and abnormal activation, which initiates downstream signaling pathways crucial in cancer cell survival and progression. As a result, numerous monoclonal antibodies have been developed to block HER3 activation and subsequent signaling pathways. While pre-clinical investigations have effectively showcased significant anti-cancer effects of HER3-targeted therapies, these therapies have had little impact on cancer patient outcomes in the clinic, except for patients with rare fusion mutations. This review offers a comprehensive description of the oncogenic functions of HER3, encompassing its structure and mediating signaling pathways. More importantly, it provides an in-depth exploration of past and ongoing clinical trials investigating HER3-targeted therapies for distinct types of cancer and discusses the tumor microenvironment and other critical determinants that may contribute to the observed suboptimal outcomes in most clinical studies using HER3-targeted therapies. Lastly, we suggest alternative approaches and the exploration of novel strategies to potentially improve the efficacy of targeting the pivotal oncogenic HER3 signaling pathway in future translational investigations.","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141547916","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}
Pub Date : 2024-05-31DOI: 10.1016/j.gendis.2024.101344
Recombinant adenovirus (rAdV) is a commonly used vector system for gene transfer. Efficient initial packaging and subsequent production of rAdV remains time-consuming and labor-intensive, possibly attributable to rAdV infection-associated oxidative stress and reactive oxygen species (ROS) production. Here, we show that exogenous GAPDH expression mitigates adenovirus-induced ROS-associated apoptosis in HEK293 cells, and expedites adenovirus production. By stably overexpressing GAPDH in HEK293 (293G) and 293pTP (293GP) cells, respectively, we demonstrated that rAdV-induced ROS production and cell apoptosis were significantly suppressed in 293G and 293GP cells. Transfection of 293G cells with adenoviral plasmid pAd-G2Luc yielded much higher titers of Ad-G2Luc at day 7 than that in HEK293 cells. Similarly, Ad-G2Luc was amplified more efficiently in 293G than in HEK293 cells. We further showed that transfection of 293GP cells with pAd-G2Luc produced much higher titers of Ad-G2Luc at day 5 than that of 293pTP cells. 293GP cells amplified the Ad-G2Luc much more efficiently than 293pTP cells, indicating that exogenous GAPDH can further augment pTP-enhanced adenovirus production. These results demonstrate that exogenous GAPDH can effectively suppress adenovirus-induced ROS and thus accelerate adenovirus production. Therefore, the engineered 293GP cells represent a superfast rAdV production system for adenovirus-based gene transfer and gene therapy.
{"title":"GAPDH suppresses adenovirus-induced oxidative stress and enables a superfast production of recombinant adenovirus","authors":"","doi":"10.1016/j.gendis.2024.101344","DOIUrl":"10.1016/j.gendis.2024.101344","url":null,"abstract":"<div><p>Recombinant adenovirus (rAdV) is a commonly used vector system for gene transfer. Efficient initial packaging and subsequent production of rAdV remains time-consuming and labor-intensive, possibly attributable to rAdV infection-associated oxidative stress and reactive oxygen species (ROS) production. Here, we show that exogenous GAPDH expression mitigates adenovirus-induced ROS-associated apoptosis in HEK293 cells, and expedites adenovirus production. By stably overexpressing GAPDH in HEK293 (293G) and 293pTP (293GP) cells, respectively, we demonstrated that rAdV-induced ROS production and cell apoptosis were significantly suppressed in 293G and 293GP cells. Transfection of 293G cells with adenoviral plasmid pAd-G2Luc yielded much higher titers of Ad-G2Luc at day 7 than that in HEK293 cells. Similarly, Ad-G2Luc was amplified more efficiently in 293G than in HEK293 cells. We further showed that transfection of 293GP cells with pAd-G2Luc produced much higher titers of Ad-G2Luc at day 5 than that of 293pTP cells. 293GP cells amplified the Ad-G2Luc much more efficiently than 293pTP cells, indicating that exogenous GAPDH can further augment pTP-enhanced adenovirus production. These results demonstrate that exogenous GAPDH can effectively suppress adenovirus-induced ROS and thus accelerate adenovirus production. Therefore, the engineered 293GP cells represent a superfast rAdV production system for adenovirus-based gene transfer and gene therapy.</p></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":null,"pages":null},"PeriodicalIF":6.9,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352304224001417/pdfft?md5=206897c8fce371b15f69ce30294d43f2&pid=1-s2.0-S2352304224001417-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141547909","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}
With the advancement of high-throughput sequencing and bioinformatics, an increasing number of overlooked small noncoding RNAs (sncRNAs) have emerged. These sncRNAs predominantly comprise transfer RNA-derived fragments (tsRNAs), PIWI-interacting RNAs (piRNAs), Ro-associated non-coding RNAs (RNYs or Y-RNAs), small nucleolar RNAs (snoRNAs), and small nuclear RNAs (snRNAs). Each of these RNA types possesses distinct biological properties and plays specific roles in both physiological and pathological processes. The differential expression of sncRNAs substantially affects the occurrence and progression of various systemic diseases. However, their roles in the cardiovascular system remain unclear. Therefore, understanding the functionality and mechanisms of sncRNAs in the cardiovascular system holds promise for identifying novel targets and strategies for the diagnosis, prevention, and treatment of cardiovascular diseases. This review examines the biological characteristics of sncRNAs and their potential roles in cardiovascular diseases.
{"title":"The significance of small noncoding RNAs in the pathogenesis of cardiovascular diseases","authors":"Hemanyun Bai, Fanji Meng, Kangling Ke, Lingyan Fang, Weize Xu, Haitao Huang, Xiao Liang, Weiyan Li, Fengya Zeng, Can Chen","doi":"10.1016/j.gendis.2024.101342","DOIUrl":"https://doi.org/10.1016/j.gendis.2024.101342","url":null,"abstract":"With the advancement of high-throughput sequencing and bioinformatics, an increasing number of overlooked small noncoding RNAs (sncRNAs) have emerged. These sncRNAs predominantly comprise transfer RNA-derived fragments (tsRNAs), PIWI-interacting RNAs (piRNAs), Ro-associated non-coding RNAs (RNYs or Y-RNAs), small nucleolar RNAs (snoRNAs), and small nuclear RNAs (snRNAs). Each of these RNA types possesses distinct biological properties and plays specific roles in both physiological and pathological processes. The differential expression of sncRNAs substantially affects the occurrence and progression of various systemic diseases. However, their roles in the cardiovascular system remain unclear. Therefore, understanding the functionality and mechanisms of sncRNAs in the cardiovascular system holds promise for identifying novel targets and strategies for the diagnosis, prevention, and treatment of cardiovascular diseases. This review examines the biological characteristics of sncRNAs and their potential roles in cardiovascular diseases.","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141253105","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}
Pub Date : 2024-05-30DOI: 10.1016/j.gendis.2024.101340
Zhenyu Xie, Gaozan Zheng, Liaoran Niu, Kunli Du, Ruikai Li, Hanjun Dan, Lili Duan, Hongze Wu, Guangming Ren, Xinyu Dou, Songchen Dai, Fan Feng, Jian Zhang, Jianyong Zheng
macrophages have been identified as key players in the colorectal cancer (CRC) tumor microenvironment, but their function remains unclear. This study integrated single-cell and spatial transcriptomics with bulk sequencing to investigate the roles and mechanisms of macrophages in CRC. Our findings revealed a pronounced elevation of macrophages in CRC, especially within tumor territories. These macrophages served as markers for CRC initiation, progression, metastasis, and potential prognosis. Furthermore, they showed heightened transcriptional activity in genes linked to angiogenesis, epithelial–mesenchymal transition, glycolysis, hypoxia, and immunosuppression. protein amplified CRC cell migration and invasion, potentially mediating cellular crosstalk via the , , and complex axes. Patients with a high proportion of macrophages could benefit more from immune checkpoint blockade therapy. Interestingly, expression was significantly enriched in macrophages versus macrophages, possibly explaining limited anti-CSF1R monotherapy effects. In conclusion, we propose an macrophage model in CRC, highlighting such macrophages as a promising therapeutic target due to their malignancy markers.
{"title":"SPP1+ macrophages in colorectal cancer: Markers of malignancy and promising therapeutic targets","authors":"Zhenyu Xie, Gaozan Zheng, Liaoran Niu, Kunli Du, Ruikai Li, Hanjun Dan, Lili Duan, Hongze Wu, Guangming Ren, Xinyu Dou, Songchen Dai, Fan Feng, Jian Zhang, Jianyong Zheng","doi":"10.1016/j.gendis.2024.101340","DOIUrl":"https://doi.org/10.1016/j.gendis.2024.101340","url":null,"abstract":"macrophages have been identified as key players in the colorectal cancer (CRC) tumor microenvironment, but their function remains unclear. This study integrated single-cell and spatial transcriptomics with bulk sequencing to investigate the roles and mechanisms of macrophages in CRC. Our findings revealed a pronounced elevation of macrophages in CRC, especially within tumor territories. These macrophages served as markers for CRC initiation, progression, metastasis, and potential prognosis. Furthermore, they showed heightened transcriptional activity in genes linked to angiogenesis, epithelial–mesenchymal transition, glycolysis, hypoxia, and immunosuppression. protein amplified CRC cell migration and invasion, potentially mediating cellular crosstalk via the , , and complex axes. Patients with a high proportion of macrophages could benefit more from immune checkpoint blockade therapy. Interestingly, expression was significantly enriched in macrophages versus macrophages, possibly explaining limited anti-CSF1R monotherapy effects. In conclusion, we propose an macrophage model in CRC, highlighting such macrophages as a promising therapeutic target due to their malignancy markers.","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141547915","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}
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