Genes & Diseases最新文献

{"title":"Chloride channel accessory 4 suppresses stem cell-like properties of colorectal cancer and enhances anti-PD-1 immunotherapy","authors":"Fang Wei ,&nbsp;Qi Zou ,&nbsp;Qihui Sun ,&nbsp;Tingting Jiang ,&nbsp;Tian Cai ,&nbsp;Xiaojia Li ,&nbsp;Keping Xie","doi":"10.1016/j.gendis.2025.101859","DOIUrl":"10.1016/j.gendis.2025.101859","url":null,"abstract":"<div><div>Reduced chloride channel accessory 4 (CLCA4) levels are linked to cancer development, while its role and mechanism in cancer stem cells (CSCs) remain unclear. In this study, we discovered that decreased CLCA4 expression was evident in CD133⁺CD44⁺ colorectal CSCs and chemoresistant colorectal cancer (CRC) cells. Increased expression of CLCA4 inhibited the expression of stemness genes, reduced tumorsphere formation, suppressed the self-renewal, migratory, and invasive capabilities of colorectal CSCs <em>in vitro</em>, and suppressed the tumorigenicity of colorectal CSCs <em>in vivo</em>. Mechanistically, CLCA4 interacted with vimentin, leading to FAK pathway inactivation and subsequent suppression of CSC expansion, while vimentin up-regulation attenuated the effects of CLCA4 down-regulation and established its role in CLCA4-mediated colorectal CSC self-renewal. Decreased CLCA4 expression was positively correlated with colorectal CSC markers and vimentin in clinical specimens. Increased CLCA4 expression promoted the infiltration of cytotoxic CD8⁺ T cells and enhanced the anti-PD-1 therapeutic efficacy. Our findings suggest that CLCA4 could impede colorectal CSC self-renewal by interacting with vimentin to suppress the FAK signaling pathway, potentially reducing tumor cell stemness and evading immune surveillance. The new findings on cellular and molecular mechanisms underpinning CRC development and progression could offer new perspectives for potential intervention and treatment of CRC.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101859"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167168","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":"Blockage of SUMO E1 enzyme inhibits ocular lens fibrosis by mediating SMAD4 SUMOylation","authors":"Min Hou ,&nbsp;Yujie Ding ,&nbsp;Xuan Bao ,&nbsp;Liangping Liu ,&nbsp;Yulan Wang ,&nbsp;Mingxing Wu","doi":"10.1016/j.gendis.2025.101827","DOIUrl":"10.1016/j.gendis.2025.101827","url":null,"abstract":"<div><div>The ocular lens serves as an exemplary biological model for investigating mechanisms of fibrotic disease, particularly through its well-characterized epithelial–mesenchymal transition (EMT) process. In lens capsular fibrosis, lens epithelial cells (LECs) undergo phenotypic transformation mediated by the dysregulation of a complex signaling network. While multiple interconnected pathways have been implicated in this pathogenic process, current therapeutic strategies for anterior subcapsular cataract and postoperative capsular opacification remain predominantly surgical, underscoring the urgent need for targeted pharmacological interventions. SUMOylation, an essential post-translational modification system, orchestrates critical cellular processes, including gene expression, genome integrity, and cell cycle progression. Emerging evidence positions SUMOylation as a critical regulator of EMT in both fibrotic disorders and oncogenesis. Building on these insights, we hypothesized that SUMO-mediated post-transitional modifications may drive LEC transdifferentiation in lens fibrotic pathologies. Our experimental findings demonstrated that elevated global SUMOylation (SUMO1/2/3 conjugates) in human anterior subcapsular cataract specimens correlated with fibrotic progression. Sole SUMO isoform deficiency partially mitigated TGFβ₂-driven EMT and injury-induced anterior subcapsular cataract. SUMO E1 overexpression enhanced LEC proliferative capacity, migration potential, and EMT progression. Pharmacological SUMO E1 inhibition (ML792) suppressed TGFβ₂-induced SMAD4 SUMOylation, nuclear translocation, a critical TGFβ/SMAD signaling event. ML792 also eliminated TGFβ₂-induced LEC EMT and experimental anterior subcapsular cataract. Our results establish SMAD4 SUMOylation as a pivotal molecular switch in lens fibrosis pathogenesis. Employing inhibitory drugs of SUMO conjugation in the years to come has the potential to be a novel therapeutic strategy for fibrotic cataracts.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101827"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167245","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":"TNFAIP8/TIPE2 inactivation modulates extracellular matrix organization gene expression and preserves the intervertebral disc structure in mice","authors":"Zuozhen Tian ,&nbsp;Ken Chen ,&nbsp;Frances S. Shofer ,&nbsp;Srish S. Chenna ,&nbsp;Daniel Z. Sandroni ,&nbsp;Ling Qin ,&nbsp;Yejia Zhang","doi":"10.1016/j.gendis.2025.101835","DOIUrl":"10.1016/j.gendis.2025.101835","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101835"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975345","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":"The molecular and immune landscape of the forkhead-box gene family in different subtypes of breast cancer","authors":"Xiaoman Bi ,&nbsp;Liyang Chen ,&nbsp;Deng Wu ,&nbsp;Dahua Xu ,&nbsp;Dehua Zheng ,&nbsp;Zhizhou Xu ,&nbsp;Zhenling Wan ,&nbsp;Shaoping Zheng ,&nbsp;Kongning Li ,&nbsp;Shaojiang Zheng","doi":"10.1016/j.gendis.2025.101911","DOIUrl":"10.1016/j.gendis.2025.101911","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101911"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973016","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":"Machine learning-based stratification of Parkinson’s disease progression using dysautonomia symptoms and transcriptomic signatures","authors":"Su-Jin Baek ,&nbsp;Hyeong Joon Jun ,&nbsp;Jae Hyeok Han ,&nbsp;SeoHyun Lee ,&nbsp;HuiYan Zhao ,&nbsp;Muhammad Umar ,&nbsp;Jae Young Jang ,&nbsp;Jung-Hee Jang","doi":"10.1016/j.gendis.2025.101831","DOIUrl":"10.1016/j.gendis.2025.101831","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101831"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024254","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":"CBS promotes tumor immune evasion by reducing MHC-I stability","authors":"Yanrong Yang ,&nbsp;Yadong Guo ,&nbsp;Shiyu Mao ,&nbsp;Chengyuan Dong ,&nbsp;Zhu Yu ,&nbsp;Xudong Yao ,&nbsp;Bing Shen","doi":"10.1016/j.gendis.2025.101782","DOIUrl":"10.1016/j.gendis.2025.101782","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101782"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024263","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":"HSP90B1 facilitates glioma radiotherapy resistance by regulating RhoC ubiquitin‒proteasome degradation","authors":"Jiacheng Xu ,&nbsp;Yuduo Guo ,&nbsp;Jingjing Yang ,&nbsp;Guanjie Shang ,&nbsp;Weihai Ning ,&nbsp;Deshan Liu ,&nbsp;Hongwei Zhang ,&nbsp;Yongmei Song","doi":"10.1016/j.gendis.2025.101756","DOIUrl":"10.1016/j.gendis.2025.101756","url":null,"abstract":"<div><div>Gliomas are primary brain tumors known for their resistance to radiotherapy and frequent recurrence. This might result from the high heterogeneity and transcriptional plasticity of gliomas. Heat shock proteins are associated with unfavorable tumor outcomes and protect tumors from the effects of radiotherapy. However, their influence on brain tumors is not fully understood. Initial analyses of glioma patients from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases who had undergone radiotherapy identified HSP90B1 as a crucial gene affecting patient prognosis. Subsequent investigations revealed that HSP90B1 enhanced the proliferation, migration, and invasion of glioma cells. It was also found to protect glioma cells from radiotherapy-induced apoptosis. Co-immunoprecipitation (CO-IP) found that HSP90B1 directly interacted with RhoC and protected it from degradation via the ubiquitin–proteasome pathway. Rescue experiments indicated that HSP90B1 might facilitate glioma migration, invasion, and radiotherapy resistance by modulating RhoC expression. A mouse model further demonstrated that gliomas expressing high levels of HSP90B1 exhibited decreased sensitivity to radiotherapy. Overall, our research revealed that HSP90B1 significantly impacts the prognosis of glioma patients treated with radiotherapy. Additionally, HSP90B1 might enhance glioma metastasis and resistance to radiotherapy by regulating RhoC expression. This regulatory effect was achieved by the directly binding of HSP90B1 to RhoC, thereby preventing its degradation through the ubiquitin–proteasome pathway.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101756"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146170448","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":"Pan-cancer analysis of ALK mutation and its association with tumor immunogenicity and the efficacy of immune checkpoint blockade","authors":"Zhiyang Huang ,&nbsp;Jiajun Chen ,&nbsp;Yan Huang ,&nbsp;Hong Zhao ,&nbsp;Bin Zhao","doi":"10.1016/j.gendis.2025.101701","DOIUrl":"10.1016/j.gendis.2025.101701","url":null,"abstract":"<div><div>Anaplastic lymphoma kinase (<em>ALK</em>) plays important roles in tumorigenesis and is involved in tumor immunogenicity through various pathways. Here, we conducted a comprehensive bioinformatic and clinical analysis on the characteristics of pan-cancer <em>ALK</em> mutation and its association with tumor immunity and the efficacy of immune checkpoint blockade. In 2930 patients with 11 tumor types treated with immune checkpoint inhibitors, the mutation of <em>ALK</em> indicated favorable overall survival (hazard ratio = 0.69; 95% confidence interval, 0.57–0.83; <em>p</em> &lt; 0.001). We further developed and validated a nomogram to estimate the 12-month and 24-month survival probabilities after the initiation of immunotherapy. Moreover, multi-omics analysis on both intrinsic and extrinsic immune landscapes revealed that the mutation of <em>ALK</em> could enrich infiltration of immune cells, enhance tumor immunogenicity, and improve immune responses. In conclusion, <em>ALK</em> mutation is associated with promoted cancer immunity and can be treated as a biomarker for favorable outcomes in pan-cancer immune checkpoint blockade. These results have implications for treatment decision-making and developing immunotherapy for personalized care.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101701"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146170449","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":"Role of miR-101a in targeting Cox-2 to attenuate chondrocyte hypertrophic differentiation and osteoarthritis progression","authors":"Rui Mi ,&nbsp;Jinnan Chen ,&nbsp;Tianxiang Zhu ,&nbsp;Huiqin Bian ,&nbsp;Rong Wei ,&nbsp;Rushuang Deng ,&nbsp;Tiaotiao Han ,&nbsp;Qian Wang ,&nbsp;Yaojuan Lu ,&nbsp;Longwei Qiao ,&nbsp;Yuting Liang ,&nbsp;Qiping Zheng","doi":"10.1016/j.gendis.2025.101839","DOIUrl":"10.1016/j.gendis.2025.101839","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally, often playing critical roles in various biological processes. Recent studies have highlighted the involvement of miRNAs in chondrogenesis by targeting key marker genes. Among these, miR-101a has been identified as a significant regulator, previously reported to target cyclooxygenase-2 (Cox-2, ptgs2) in various contexts. Here, we investigate the role of miR-101a in chondrocyte hypertrophy and osteoarthritis (OA) progression, focusing on its regulation of Col10a1 expression. Using multiple web-based tools (TargetScan, PicTar, miRDB, and miRCODE), we identified miR-101a as a potential regulator of Col10a1. Our <em>in vitro</em> experiments demonstrated that miR-101a was down-regulated during chondrocyte hypertrophy in MCT and ATDC5 cells, while Col10a1 and Cox-2 expression levels were up-regulated. Overexpression of miR-101a via mimics resulted in a significant decrease in Col10a1 and Cox-2 at both mRNA and protein levels, whereas inhibition of miR-101a led to their up-regulation. Additionally, MMP-13 protein levels were reduced upon miR-101a overexpression, with no significant changes in Sox9 and Runx2 expression. Luciferase reporter assays confirmed that Cox-2 was a direct target of miR-101a, suggesting that miR-101a indirectly regulates Col10a1 expression via Cox-2. <em>In vivo</em>, intra-articular injection of miR-101a mimics in a medial meniscus-induced OA mouse model resulted in decreased Col10a1 expression and reduced articular damage, supporting the protective role of miR-101a in OA progression. Our findings highlight miR-101a as a negative regulator of chondrocyte hypertrophy through Cox-2, and could be a potential target for further exploration in OA therapy.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101839"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167234","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":"Molecular characterization of a new R1925X point mutation mouse model for dysferlinopathy","authors":"Camille Bouchard ,&nbsp;Louis Despax ,&nbsp;Joël Rousseau ,&nbsp;Jacques P. Tremblay","doi":"10.1016/j.gendis.2025.101885","DOIUrl":"10.1016/j.gendis.2025.101885","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 3","pages":"Article 101885"},"PeriodicalIF":9.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145973018","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}