Neoplasia最新文献

{"title":"Global, regional and national burden of neuroblastoma and other peripheral nervous system tumors, 1990 to 2021 and predictions to 2035: visualizing epidemiological characteristics based on GBD 2021","authors":"Chaoyan Yue ,&nbsp;Qi Zhang ,&nbsp;Fenyong Sun ,&nbsp;Qiuhui Pan","doi":"10.1016/j.neo.2025.101122","DOIUrl":"10.1016/j.neo.2025.101122","url":null,"abstract":"<div><h3>Background</h3><div>Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children, accounting for &gt;15 % of cancer-related deaths in children. We analyzed the epidemiological statistical indicators of neuroblastoma and other peripheral nervous system tumors patients from 1990 to 2021 in Global Burden of Disease (GBD) 2021 database, aiming to provide valuable insights for public health interventions and clinical practices.</div></div><div><h3>Methods</h3><div>Based on the GBD 2021 database, this study analyzed the incidence, mortality, prevalence, and Disability-Adjusted Life-Years (DALYs) of neuroblastoma and other peripheral nervous system tumors from 1990 to 2021, stratified by sociodemographic development index (SDI) and geographic regions. Cross-country inequalities analysis was conducted to quantify the SDI-related inequality of disease burden across countries. In addition, the average annual percentage change (AAPC) and Age-Period-Cohort (APC) model were used to evaluate the trend of disease burden, while the global burden of disease to 2035 was predicted by Bayesian Age-Period-Cohort (BAPC) model.</div></div><div><h3>Findings</h3><div>This study reported the disease burden of neuroblastoma and other peripheral nervous system tumors in GBD 2021 database for the first time. Globally, the incidence and mortality of neuroblastoma have increased year by year from 1990 to 2021, especially in regions with low SDI, such as South Asia and sub-Saharan Africa, where the burden of disease has increased significantly. Regions with high SDI, such as North America and Western Europe, have seen a reduction in disease burden due to higher levels of medical care and earlier diagnosis. The age distribution shows that children under 5 years of age are mainly affected, especially in low- and middle-income areas. In addition, the incidence is slightly higher in men than in women. The BAPC model predicts that the global incidence, mortality, and DALYs of neuroblastoma will continue to increase until 2035.</div></div><div><h3>Interpretation</h3><div>Significant regional and population variation in neuroblastoma and other peripheral nervous system tumors worldwide, with a particularly high disease burden in low SDI areas with limited medical resources. This trend highlights the urgent need for global public health interventions and resource allocation, particularly in low-income countries. Future research should focus on improving early diagnosis, risk stratification and target therapy in order to reduce the global burden of disease and improve patients’ prognosis.</div></div><div><h3>Funding</h3><div>This study was supported by <span>National Natural Science Foundation of China</span> (No. 82293662, No 82172357 and No 81930066), Key project of Shanghai \"Science and Technology Innovation Action Plan (22JC1402304) and Research fund of Shanghai Municipal Health Bureau (No. 2019cxjq03).</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101122"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042423","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":"Corrigendum to “Depletion of ß1,6-N-acetylglucosaminyltransferase reduces E-selectin binding capacity and migratory potential of human gastrointestinal adenocarcinoma cells” [Neoplasia 59 (2024) 10183]","authors":"Lisa Staffeldt ,&nbsp;Hanna Maar ,&nbsp;Julia Beimdiek ,&nbsp;Samuel Chambers ,&nbsp;Kristoffer Riecken ,&nbsp;Mark von Itzstein ,&nbsp;Falk FR Buettner ,&nbsp;Arun Everest-Dass ,&nbsp;Tobias Lange","doi":"10.1016/j.neo.2025.101124","DOIUrl":"10.1016/j.neo.2025.101124","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101124"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014462","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":"Comparison of differences in transcriptional and genetic profiles between intra-central nervous system and extra-central nervous system large B-cell lymphoma","authors":"Shu Wang ,&nbsp;Hong Chen ,&nbsp;Bo Dai ,&nbsp;Kang Zheng ,&nbsp;Jiajun Zheng ,&nbsp;Yuqi Zhu ,&nbsp;Yan Yuan ,&nbsp;Tianling Ding ,&nbsp;Qian Wang ,&nbsp;Liqian Xie ,&nbsp;Rui Feng ,&nbsp;Fengping Zhu ,&nbsp;Jianbin Xiang ,&nbsp;Weiqun Ding ,&nbsp;Hong Ding ,&nbsp;Yuan Li ,&nbsp;Xiaodong Gu ,&nbsp;Kunpeng Wu ,&nbsp;Yifan Yuan ,&nbsp;Jianping Song ,&nbsp;Tong Chen","doi":"10.1016/j.neo.2024.101119","DOIUrl":"10.1016/j.neo.2024.101119","url":null,"abstract":"<div><div>Primary central nervous system diffused large B-cell lymphoma (PCNS-DLBCL) is a rare type of non-Hodgkin lymphoma restricted to the central nervous system (CNS). To explore its specific pathogenesis and therapeutic targets, we performed multi-omics sequencing on tumor samples from patients diagnosed with PCNS-DLBCL, secondary CNS-DLBCL or extracranial (ec) DLBCL.By single-cell RNA sequencing, highly proliferated and dark zone (DZ)-related B cell subclusters, MKI67_B1, PTTG1_B2 and BTG1_B3, were predominant significantly in PCNS-DLBCL. Compared to SCNS-DLBCL and ecDLBCL, an immune-suppressive tumor microenvironment was observed in PCNS-DLBCL by analysis of immune-stimulating/inhibitory ligand‒receptor (L-R) pairs. By performing whole-exome sequencing in 93 patients, mutations enriched in BCR-NFkB and TLR pathways and the cooperation of these two pathways were found to be predominant in PCNS-DLBCL comparing to nonGCB-ecDLBCL. In summary, our study provides comprehensive insights into the transcriptomic and genetic characteristics of PCNS-DLBCL in contrast to ecDLBCL and will help dissect the oncogenic mechanism of this disease.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101119"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904021","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":"Tumor-Infiltrating Immune Cells in Colorectal Cancer","authors":"Sonia A.M. Ferkel,&nbsp;Elizabeth A. Holman,&nbsp;Raoul S. Sojwal,&nbsp;Samuel J.S. Rubin,&nbsp;Stephan Rogalla","doi":"10.1016/j.neo.2024.101091","DOIUrl":"10.1016/j.neo.2024.101091","url":null,"abstract":"<div><div>Colorectal cancer encompasses a heterogeneous group of malignancies that differ in pathophysiological mechanisms, immune response and infiltration, therapeutic response, and clinical prognosis. Numerous studies have highlighted the clinical relevance of tumor-infiltrating immune cells among different types of colorectal tumors yet vary in cell type definitions and cell identification strategies. The distinction of immune signatures is particularly challenging when several immune subtypes are involved but crucial to identify novel intercellular mechanisms within the tumor microenvironment. In this review, we compile human and non-human studies on tumor-infiltrating immune cells and provide an overview of immune subtypes, their pathophysiological functions, and their prognostic role in colorectal cancer. We discuss how differentiating immune signatures can guide the development of immunotherapeutic targets and personalized treatment regimens. We analyzed comprehensive human protein biomarker profiles across the entire immune spectrum to improve interpretability and application of tumor studies and to ultimately enhance immunotherapy and advance precision medicine for colorectal cancer patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101091"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11665540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792638","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":"circUBR5 promotes ribosome biogenesis and induces docetaxel resistance in triple-negative breast cancer cell lines via the miR-340-5p/CMTM6/c-MYC axis","authors":"Xuedong Wang ,&nbsp;Xinping Wang ,&nbsp;Juan Gu ,&nbsp;Yilei Wei ,&nbsp;Yueping Wang","doi":"10.1016/j.neo.2024.101062","DOIUrl":"10.1016/j.neo.2024.101062","url":null,"abstract":"<div><h3>Objective</h3><div>Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways.</div></div><div><h3>Methods</h3><div>DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated.</div></div><div><h3>Results</h3><div>CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6.</div></div><div><h3>Conclusion</h3><div>circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101062"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822730","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":"Ovulation sources ROS to confer mutagenic activities on the TP53 gene in the fallopian tube epithelium","authors":"Kanchana Subramani ,&nbsp;Hsuan-Shun Huang ,&nbsp;Pao-Chu Chen ,&nbsp;Dah-Ching Ding ,&nbsp;Tang-Yuan Chu","doi":"10.1016/j.neo.2024.101085","DOIUrl":"10.1016/j.neo.2024.101085","url":null,"abstract":"<div><h3>Introduction</h3><div>Epidemiological studies have implicated ovulation as a risk factor for ovarian high-grade serous carcinoma (HGSC) at the initiation stage. Precancerous lesions of HGSC commonly exhibit TP53 mutations attributed to DNA deamination and are frequently localized in the fallopian tube epithelium (FTE), a site regularly exposed to ovulatory follicular fluid (FF). This study aimed to assess the mutagenic potential of FF and investigate the expression levels and functional role of activation-induced cytidine deaminase (AID) following ovulation, along with the resulting TP53 DNA deamination.</div></div><div><h3>Methods</h3><div>The mutagenic activity of FF toward premalignant and malignant FTE cells was determined using the hypoxanthine phosphoribosyl transferase (HPRT) mutation assay with or without AID knockdown. The sequential activation of AID, including expressional induction, nuclear localization, DNA binding, and deamination, was determined. AID inducers in FF were identified, and the times of action and signaling pathways were determined.</div></div><div><h3>Results</h3><div>FF induced AID activation and <em>de novo</em> FTE cell mutagenesis in two waves of activity in accordance with post-ovulation FF exposure. The ERK-mediated early activity started at 2 min and peaked at 45 min, and the NF-κB-mediated late activity started at 6 h and peaked at 8.5 h after exposure. ROS, TNF-α, and estradiol, which are abundant in FF, all induced the two activities, while all activities were abolished by antioxidant cotreatment. AID physically bound to and biochemically deaminated the <em>TP53</em> gene, regardless of known mutational hotspots. It did not act on other prevalent tumor-suppressor genes of HGSC.</div></div><div><h3>Conclusion</h3><div>This study revealed the ROS-dependent AID-mediated mutagenic activity of the ovulatory FF. The results filled up the missing link between ovulation and the initial <em>TP53</em> mutation and invited a strategy of antioxidation in prevention of HGSC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101085"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787442","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":"Pediatric neuro-oncology: Highlights of the last quarter-century","authors":"Phoebe Power ,&nbsp;Joelle P Straehla ,&nbsp;Jason Fangusaro ,&nbsp;Pratiti Bandopadhayay ,&nbsp;Neevika Manoharan","doi":"10.1016/j.neo.2024.101098","DOIUrl":"10.1016/j.neo.2024.101098","url":null,"abstract":"<div><div>The last quarter century has heralded dramatic changes in the field of pediatric neuro-oncology, with the era defined by profound developments in the understanding of the biological underpinnings of childhood central nervous system (CNS) tumors and translational therapeutics. Although there have been momentous strides forward in biologic, diagnostic, therapeutic, and experimental domains, considerable challenges remain and CNS tumors remain the leading cause of pediatric cancer-related mortality. Here, we review the significant advances in the field of pediatric neuro-oncology over the last 25 years and highlight ongoing hurdles facing future progress.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101098"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787444","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":"Porcupine expression promotes the progression of oral carcinogenesis","authors":"Daniel Peña-Oyarzún ,&nbsp;Andrew F.G. Quest ,&nbsp;Lorena Lobos-González ,&nbsp;Andrea Maturana-Ramírez ,&nbsp;Montserrat Reyes","doi":"10.1016/j.neo.2024.101097","DOIUrl":"10.1016/j.neo.2024.101097","url":null,"abstract":"<div><div>Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, which is usually preceded by a potentially malignant disorder histologically diagnosed as dysplasia. We and others have provided evidence for the pro-carcinogenic role of the Wnt/β-catenin pathway in this context, in which Wnt ligands stabilize and allow relocalization of β-catenin to the nucleus for transcription of pro-survival and pro-proliferation genes. However, the contribution of Porcupine (PORCN), an O-acyltransferase that catalyzes the palmitoylation of Wnt ligands, to OSCC carcinogenesis is not known. Moreover, the effectiveness of LGK974, a novel PORCN inhibitor remains to be elucidated. By using different <em>ex vivo, in vivo</em> and <em>in vitro</em> OSCC carcinogenesis models, we show that PORCN expression is significantly increased in high-grade dysplasia as well as moderately/poorly- differentiated OSCC. Consistent with these observations, expression of key proteins involved in the Wnt/β-catenin pathway are elevated as well. Importantly, the treatment with LGK974, a chemical PORCN inhibitor, reduced the number and size of oral lesions in mice treated with 4-Nitroquinoline 1-oxide (4NQO), a tobacco smoke surrogate. These results highlight the role of PORCN during OSCC carcinogenesis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101097"},"PeriodicalIF":4.8,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756835","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":"XAF1 is secreted from stressed tumor cells to activate T cell-mediated tumor surveillance via Lck-ERK signaling","authors":"Jieun Ahn,&nbsp;Seung-Hun Jang,&nbsp;Sungchan Jang,&nbsp;Ji-Hye Yoon,&nbsp;Min-Goo Lee,&nbsp;Sung-Gil Chi","doi":"10.1016/j.neo.2024.101094","DOIUrl":"10.1016/j.neo.2024.101094","url":null,"abstract":"<div><div>X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in multiple types of human malignancies. Nevertheless, the molecular basis for the XAF1-mediated tumor suppression remains largely undefined. Here, we report that XAF1 is secreted from cells under various cytotoxic stress conditions and activates T cell-mediated tumor surveillance. In cancer cells exposed to interferon <span><math><mrow><mo>−</mo><mi>γ</mi></mrow></math></span>, tumor necrosis factor <span><math><mrow><mo>−</mo><mi>α</mi></mrow></math></span>, and etoposide, XAF1 is elevated and actively secreted through the unconventional endo-lysosomal trafficking pathway and the zinc finger 4 domain of XAF1 plays an essential for this secretion. Secreted XAF1 is internalized into nearby T cells through clathrin-mediated endocytosis and stimulates proliferation, migration, and tumor infiltration of T cells. Internalized XAF1 activates RAF-MEK-ERK signaling through the direct interaction with and phosphorylation of lymphocyte-specific protein tyrosine kinase. In response to interferon <span><math><mrow><mo>−</mo><mi>γ</mi></mrow></math></span> injection, <em>Xaf1</em>^<em>+</em>^<em>/+</em> tumors display significantly higher regression rate and T cell infiltration compared to <em>Xaf1^−/−</em> tumors while <em>Xaf1</em>^−/− tumors are markedly reduced by injection of recombinant Xaf1. XAF1 expression is associated with overall survival in T cell-enriched cancer patients and also correlates with prognosis in T cell-based immunotherapies. Together, our study identifies XAF1 as a novel secretory immune-modulatory tumor suppressor, illuminating the mechanistic consequence of its inactivation in tumorigenesis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101094"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743804","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":"Suppression of ADP-ribosylation reversal triggers cell vulnerability to alkylating agents","authors":"Rocco Caggiano ,&nbsp;Evgeniia Prokhorova ,&nbsp;Lena Duma ,&nbsp;Kira Schützenhofer ,&nbsp;Raffaella Lauro ,&nbsp;Giuliana Catara ,&nbsp;Rosa Marina Melillo ,&nbsp;Angela Celetti ,&nbsp;Rebecca Smith ,&nbsp;S John Weroha ,&nbsp;Scott H Kaufmann ,&nbsp;Ivan Ahel ,&nbsp;Luca Palazzo","doi":"10.1016/j.neo.2024.101092","DOIUrl":"10.1016/j.neo.2024.101092","url":null,"abstract":"<div><div>The ADP-ribosyl hydrolases PARG and ARH3 counteract PARP enzymatic activity by removing ADP-ribosylation. PARG and ARH3 activities have a synthetic lethal effect; however, the specific molecular mechanisms underlying this response remain unknown. Here, we show that the PARG and ARH3 synthetic lethality is enhanced further in the presence of DNA alkylating agents, suggesting that the inability to revert ADP-ribosylation primarily affects the repair of alkylated DNA bases. <em>ARH3</em> knockout cells, treated with PARG inhibitor and alkylating genotoxins, accumulated single-stranded DNA and DNA damage, resulting in G2/M cell cycle arrest and apoptosis. Furthermore, we reveal a reduction in PARP1/PARP2 levels in <em>ARH3</em>-deficient cells treated with PARG inhibitor due to excessive ADP-ribosylation, which may contribute to alkylating agents’ vulnerability. Collectively, these results uncover the potential of targeting ADP-ribosyl hydrolases in combination with alkylating agents for cancer therapy and provide insights into the mechanisms underlying the synthetic lethal effect.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101092"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743818","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}