Pub Date : 2025-06-18DOI: 10.1016/j.gendis.2025.101718
Dandan Xu , Zihan Huang , Gaojia Zhang , Jiao Jiao , Yujia Cao , Mengyu Liu , Yan Kong , Zhijun Zhang
Major depressive disorder (MDD) is a serious mental disorder, yet the mechanism by which circular RNAs (circRNAs) are involved in the pathogenesis of MDD by encoding proteins is unknown. Our previous study has shown that circFKBP8(5S,6) relies on its encoded protein, namely cFKBP8, to promote susceptibility to chronic unpredictable mild stress (CUMS) in mice, but the precise molecular mechanisms are unknown. Here we found that overexpression of circFKBP8(5S,6) or cFKBP8 in neurons of the prelimbic cortex (PrL) of CUMS mice down-regulated the expression levels of DRD3 and its downstream AMPK/ULK1 (Ser555) and AMPK/mTOR/ULK1 (Ser757) pathways, which resulted in down-regulation of neuronal autophagy levels. Interestingly, both the activation and overexpression of DRD3 ameliorated the exacerbation of depressive-like behaviors induced by circFKBP8(5S,6) or cFKBP8, activated both the AMPK/ULK1 (Ser555) pathway and the AMPK/mTOR/ULK1 (Ser757) pathway, and up-regulated neuronal autophagy levels. In conclusion, circFKBP8(5S,6) or cFKBP8 promotes susceptibility to CUMS in mice, at least in part, by down-regulating DRD3 expression and its downstream AMPK/mTOR/ULK1 signaling pathway-mediated neuronal autophagy.
{"title":"circFKBP8(5S,6)-encoded protein promotes stress susceptibility in mice by down-regulating dopamine D3 receptor expression and its downstream AMPK/mTOR/ULK1 autophagy signaling","authors":"Dandan Xu , Zihan Huang , Gaojia Zhang , Jiao Jiao , Yujia Cao , Mengyu Liu , Yan Kong , Zhijun Zhang","doi":"10.1016/j.gendis.2025.101718","DOIUrl":"10.1016/j.gendis.2025.101718","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is a serious mental disorder, yet the mechanism by which circular RNAs (circRNAs) are involved in the pathogenesis of MDD by encoding proteins is unknown. Our previous study has shown that circFKBP8(5S,6) relies on its encoded protein, namely cFKBP8, to promote susceptibility to chronic unpredictable mild stress (CUMS) in mice, but the precise molecular mechanisms are unknown. Here we found that overexpression of circFKBP8(5S,6) or cFKBP8 in neurons of the prelimbic cortex (PrL) of CUMS mice down-regulated the expression levels of DRD3 and its downstream AMPK/ULK1 (Ser555) and AMPK/mTOR/ULK1 (Ser757) pathways, which resulted in down-regulation of neuronal autophagy levels. Interestingly, both the activation and overexpression of DRD3 ameliorated the exacerbation of depressive-like behaviors induced by circFKBP8(5S,6) or cFKBP8, activated both the AMPK/ULK1 (Ser555) pathway and the AMPK/mTOR/ULK1 (Ser757) pathway, and up-regulated neuronal autophagy levels. In conclusion, circFKBP8(5S,6) or cFKBP8 promotes susceptibility to CUMS in mice, at least in part, by down-regulating DRD3 expression and its downstream AMPK/mTOR/ULK1 signaling pathway-mediated neuronal autophagy.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 2","pages":"Article 101718"},"PeriodicalIF":9.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733012","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 : 2025-06-18DOI: 10.1016/j.gendis.2025.101721
Jing Cai , Li Rong , Runzhi Wang , Zaikuan Zhang , Haiming Sun , Juan Chen , Dunchu Weng , Xinyi Li , Xiaosong Feng , Peiyi Lin , Shengming Xu , Zhihong Jiang , Yajun Xie , Qin Zhou
Although Chromosome 1 open reading frame 122 (C1orf122) is known to be a protein-coding gene, its biological functions and mechanisms in hepatocellular carcinoma (HCC) remain unknown. Herein, bioinformatics analysis and experimental validation revealed that, C1orf122 was overexpressed in HCC tissues and cells, and correlated strongly with a poor prognosis of HCC patients. Subsequently, we knocked down and overexpressed C1orf122 in HCC cells, confirmed that C1orf122 significantly stimulated HCC cell growth and proliferation. Furthermore, flow cytometry and WB detection confirmed that C1orf122 significantly suppressed HCC cell apoptosis. Transwell migration and wound healing assays, along with WB analysis showed that C1orf122 strongly improved HCC cell migratory capacity. Mass spectrometry (MS) and Co-Immunoprecipitation (Co-IP) assays identified serine/arginine-rich protein-specific kinase 1 (SRPK1) as a C1orf122-interacting protein. Moreover, C1orf122 significantly upregulated total SRPK1 levels and suppressed SRPK1 protein phosphorylation at the Thr601 site. Using online prediction tools, we found that mTOR was the kinase of SRPK1 phosphorylating it at the Thr601 site, and other experiments confirmed that C1orf122 mediated SRPK1 Thr601 phosphorylation in a mTOR kinase-dependent manner. The cell phenotype assays further revealed that SRPK1 strongly stimulated the PI3K/AKT/GSK3β signaling pathway to enhance cell growth and migration. It was also observed that C1orf122 significantly activated the PI3K/AKT/GSK3β signaling pathway via SRPK1. To the best of our knowledge, this is the first study to demonstrate the involvement of the C1orf122-SRPK1-PI3K/AKT/GSK3β axis in HCC growth.
{"title":"Identifying C1orf122 as a potential HCC exacerbated biomarker dependently of SRPK1 regulates PI3K/AKT/GSK3β signaling pathway","authors":"Jing Cai , Li Rong , Runzhi Wang , Zaikuan Zhang , Haiming Sun , Juan Chen , Dunchu Weng , Xinyi Li , Xiaosong Feng , Peiyi Lin , Shengming Xu , Zhihong Jiang , Yajun Xie , Qin Zhou","doi":"10.1016/j.gendis.2025.101721","DOIUrl":"10.1016/j.gendis.2025.101721","url":null,"abstract":"<div><div>Although Chromosome 1 open reading frame 122 (C1orf122) is known to be a protein-coding gene, its biological functions and mechanisms in hepatocellular carcinoma (HCC) remain unknown. Herein, bioinformatics analysis and experimental validation revealed that, C1orf122 was overexpressed in HCC tissues and cells, and correlated strongly with a poor prognosis of HCC patients. Subsequently, we knocked down and overexpressed C1orf122 in HCC cells, confirmed that C1orf122 significantly stimulated HCC cell growth and proliferation. Furthermore, flow cytometry and WB detection confirmed that C1orf122 significantly suppressed HCC cell apoptosis. Transwell migration and wound healing assays, along with WB analysis showed that C1orf122 strongly improved HCC cell migratory capacity. Mass spectrometry (MS) and Co-Immunoprecipitation (Co-IP) assays identified serine/arginine-rich protein-specific kinase 1 (SRPK1) as a C1orf122-interacting protein. Moreover, C1orf122 significantly upregulated total SRPK1 levels and suppressed SRPK1 protein phosphorylation at the Thr601 site. Using online prediction tools, we found that mTOR was the kinase of SRPK1 phosphorylating it at the Thr601 site, and other experiments confirmed that C1orf122 mediated SRPK1 Thr601 phosphorylation in a mTOR kinase-dependent manner. The cell phenotype assays further revealed that SRPK1 strongly stimulated the PI3K/AKT/GSK3β signaling pathway to enhance cell growth and migration. It was also observed that C1orf122 significantly activated the PI3K/AKT/GSK3β signaling pathway via SRPK1. To the best of our knowledge, this is the first study to demonstrate the involvement of the C1orf122-SRPK1-PI3K/AKT/GSK3β axis in HCC growth.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 1","pages":"Article 101721"},"PeriodicalIF":9.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145320684","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 : 2025-06-14DOI: 10.1016/j.gendis.2025.101717
Zhiyuan Jin , Li Yuan , Yubo Ma , Zu Ye , Zhao Zhang , Yi Wang , Can Hu , Jinyun Dong , Xinuo Zhang , Zhiyuan Xu , Yian Du , Xiaoqing Guan , Guangzhao Pan , Sichao Tian , Juan Li , Ruiwen Zhang , Jiang-Jiang Qin , Xiangdong Cheng
Gastric signet ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer with unique epidemiological and pathogenic characteristics. However, its prognostic features and molecular landscape remain poorly understood, limiting the development of targeted therapies. In this study, we analyzed clinical data from over 10,000 patients with gastric cancer treated at Zhejiang Cancer Hospital between January 2010 and December 2019. A comprehensive proteomic analysis was conducted on 112 GSRCC patients with a signet ring cell content exceeding 70%, identifying 7322 proteins. This study established a tissue-specific peptide spectral library, representing the most extensive proteomic atlas of GSRCC to date. We identified four novel proteomic subtypes: metabolism, microenvironment dysregulation, migration, and proliferation. Furthermore, PRDX2 and DDX27 emerged as potential prognostic biomarkers, which were further validated in an independent cohort of 75 patients. Molecular profiling of 79 cases that lacked expression of established gastric cancer treatment targets and biomarkers revealed significant tumor heterogeneity. Unsupervised clustering identified three distinct proteomic clusters, with cluster 2 exhibiting the poorest prognosis. Additionally, we identified four potential drug targets, including PFAS, EIF2S3, EIF6, and NFKB2. Molecular docking analysis suggested that neratinib, a clinically approved drug, could serve as a promising therapeutic agent for GSRCC, offering new avenues for clinical intervention.
{"title":"A comprehensive proteomic analysis uncovers novel molecular subtypes of gastric signet ring cell carcinoma: Identification of potential prognostic biomarkers and therapeutic targets","authors":"Zhiyuan Jin , Li Yuan , Yubo Ma , Zu Ye , Zhao Zhang , Yi Wang , Can Hu , Jinyun Dong , Xinuo Zhang , Zhiyuan Xu , Yian Du , Xiaoqing Guan , Guangzhao Pan , Sichao Tian , Juan Li , Ruiwen Zhang , Jiang-Jiang Qin , Xiangdong Cheng","doi":"10.1016/j.gendis.2025.101717","DOIUrl":"10.1016/j.gendis.2025.101717","url":null,"abstract":"<div><div>Gastric signet ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer with unique epidemiological and pathogenic characteristics. However, its prognostic features and molecular landscape remain poorly understood, limiting the development of targeted therapies. In this study, we analyzed clinical data from over 10,000 patients with gastric cancer treated at Zhejiang Cancer Hospital between January 2010 and December 2019. A comprehensive proteomic analysis was conducted on 112 GSRCC patients with a signet ring cell content exceeding 70%, identifying 7322 proteins. This study established a tissue-specific peptide spectral library, representing the most extensive proteomic atlas of GSRCC to date. We identified four novel proteomic subtypes: metabolism, microenvironment dysregulation, migration, and proliferation. Furthermore, PRDX2 and DDX27 emerged as potential prognostic biomarkers, which were further validated in an independent cohort of 75 patients. Molecular profiling of 79 cases that lacked expression of established gastric cancer treatment targets and biomarkers revealed significant tumor heterogeneity. Unsupervised clustering identified three distinct proteomic clusters, with cluster 2 exhibiting the poorest prognosis. Additionally, we identified four potential drug targets, including PFAS, EIF2S3, EIF6, and NFKB2. Molecular docking analysis suggested that neratinib, a clinically approved drug, could serve as a promising therapeutic agent for GSRCC, offering new avenues for clinical intervention.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 1","pages":"Article 101717"},"PeriodicalIF":9.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145320685","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 : 2025-06-13DOI: 10.1016/j.gendis.2025.101726
Lijin Chen , Yingying Li , Hong Zhao , Jinyuan Huang , Huimeng Yan , Xiaoyan Lin , Bin Zhao
{"title":"Corrigendum to “Pan-cancer analysis of MET mutation and its association with the efficacy of immune checkpoint blockade” [Genes & Dis 12 (2025) 101450]","authors":"Lijin Chen , Yingying Li , Hong Zhao , Jinyuan Huang , Huimeng Yan , Xiaoyan Lin , Bin Zhao","doi":"10.1016/j.gendis.2025.101726","DOIUrl":"10.1016/j.gendis.2025.101726","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 6","pages":"Article 101726"},"PeriodicalIF":9.4,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144830432","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 : 2025-06-13DOI: 10.1016/j.gendis.2025.101720
Han Wei , Aishat Motolani , Kenneth P. Nephew , Guanglong Jiang , Faranak Alipourgivi , Steven Sun , Xiumei Huang , Mateusz Opyrchal , George Sandusky , Yunlong Liu , Tao Lu
{"title":"Forward genetics identifies HN1L/JPT2 as a novel carboplatin resistance gene in ovarian cancer","authors":"Han Wei , Aishat Motolani , Kenneth P. Nephew , Guanglong Jiang , Faranak Alipourgivi , Steven Sun , Xiumei Huang , Mateusz Opyrchal , George Sandusky , Yunlong Liu , Tao Lu","doi":"10.1016/j.gendis.2025.101720","DOIUrl":"10.1016/j.gendis.2025.101720","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 1","pages":"Article 101720"},"PeriodicalIF":9.4,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096759","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 : 2025-06-11DOI: 10.1016/j.gendis.2025.101700
Lifeng Li , Yaqi Yang , Mengle Peng , Zhirui Fan , Xiaoran Duan , Ruyue Xue , Xuefeng Lv , Ming Cheng , Jie Zhao
{"title":"Role of angiogenesis-related lncRNAs in tumor microenvironment and prognosis of lung adenocarcinoma","authors":"Lifeng Li , Yaqi Yang , Mengle Peng , Zhirui Fan , Xiaoran Duan , Ruyue Xue , Xuefeng Lv , Ming Cheng , Jie Zhao","doi":"10.1016/j.gendis.2025.101700","DOIUrl":"10.1016/j.gendis.2025.101700","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"12 6","pages":"Article 101700"},"PeriodicalIF":6.9,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144632954","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 : 2025-06-10DOI: 10.1016/j.gendis.2025.101719
Tingting Liu , Jingwen Li , Haojie Wu , Junbo Qiao , Jianshe Wei
Parkinson's disease (PD) is a complex neurodegenerative disorder that poses significant burden on patients and families. Its exact cause is unknown, resulting in limited effective treatments. Mitochondrial dysfunction, linked to genetics, aging, oxidative stress, and environmental factors, is central to PD. Healthy elderly individuals have a compensatory mitochondrial DNA (mtDNA) mechanism in brain cells, but this mechanism is impaired in PD patients, leading to mtDNA reduction, respiratory chain dysfunction, decreased adenosine triphosphate (ATP) synthesis, and inadequate neuron energy. Aging increases oxidative stress, impairing mitochondrial function. Mitochondrial dysfunction in the dopaminergic neurons of the substantia nigra causes neuronal loss and disease progression. Aging microglia also play a crucial role, with a reduced capacity to clear neurotoxic substances, especially in the substantia nigra. A decrease in triggering receptor expressed on myeloid cells 2 (TREM2) gene expression shifts microglia to a pro-inflammatory phenotype, exacerbating neuroinflammatory responses and protein deposition. Down-regulation of the C-X3-C motif chemokine ligand 1 (CX3CL1)/C-X3-C chemokine receptor 1 (CX3CR1) signaling pathway increases the expression of pro-inflammatory cytokines, accelerating neuronal loss and disease progression. Recent research has identified a new astrocyte aging regulatory mechanism involving the cyclic GMP‒AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, promoting astrocyte aging and exacerbating dopamine neuronal loss and motor dysfunction. Understanding PD pathogenesis, especially mitochondrial dysfunction, aging, and glial cell changes, is crucial for developing effective treatments.
{"title":"Unraveling Parkinson's disease: The mystery of mitochondria and the role of aging","authors":"Tingting Liu , Jingwen Li , Haojie Wu , Junbo Qiao , Jianshe Wei","doi":"10.1016/j.gendis.2025.101719","DOIUrl":"10.1016/j.gendis.2025.101719","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a complex neurodegenerative disorder that poses significant burden on patients and families. Its exact cause is unknown, resulting in limited effective treatments. Mitochondrial dysfunction, linked to genetics, aging, oxidative stress, and environmental factors, is central to PD. Healthy elderly individuals have a compensatory mitochondrial DNA (mtDNA) mechanism in brain cells, but this mechanism is impaired in PD patients, leading to mtDNA reduction, respiratory chain dysfunction, decreased adenosine triphosphate (ATP) synthesis, and inadequate neuron energy. Aging increases oxidative stress, impairing mitochondrial function. Mitochondrial dysfunction in the dopaminergic neurons of the substantia nigra causes neuronal loss and disease progression. Aging microglia also play a crucial role, with a reduced capacity to clear neurotoxic substances, especially in the substantia nigra. A decrease in triggering receptor expressed on myeloid cells 2 (TREM2) gene expression shifts microglia to a pro-inflammatory phenotype, exacerbating neuroinflammatory responses and protein deposition. Down-regulation of the C-X3-C motif chemokine ligand 1 (CX3CL1)/C-X3-C chemokine receptor 1 (CX3CR1) signaling pathway increases the expression of pro-inflammatory cytokines, accelerating neuronal loss and disease progression. Recent research has identified a new astrocyte aging regulatory mechanism involving the cyclic GMP‒AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, promoting astrocyte aging and exacerbating dopamine neuronal loss and motor dysfunction. Understanding PD pathogenesis, especially mitochondrial dysfunction, aging, and glial cell changes, is crucial for developing effective treatments.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 2","pages":"Article 101719"},"PeriodicalIF":9.4,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680821","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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