Oncogenesis最新文献

{"title":"Sphingosine 1-phosphate signalling in cancer stem cells.","authors":"Jason A Powell, Stuart M Pitson","doi":"10.1038/s41389-025-00585-y","DOIUrl":"10.1038/s41389-025-00585-y","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) are considered the head of a hierarchical organisation of carcinogenesis, exhibiting heightened cell survival properties, an ability to endlessly self-renew and undergo attenuated differentiation to maintain the bulk tumour population. The acquisition of cancer stem cell properties including dysregulated self-renewal and differentiation trajectories, is a dynamic disease-specific process underpinned by numerous genetic changes and signalling network aberrations. The bioactive sphingolipid, sphingosine 1-phosphate (S1P), has emerged as a key regulator of CSC biology. Historically, S1P has been associated with maintaining tissue homeostasis and immune responses, but recent studies have revealed that dysregulation of S1P-mediated cellular signalling plays important roles in CSC biology. This review provides an overview of the role of S1P in stem cell biology in both normal physiology and disease. It also describes approaches to target this signalling pathway, where aberrant, with the goal of eradicating the CSC population responsible for cancer initiation and progression, and importantly, patient relapse to many clinical therapeutics.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"42"},"PeriodicalIF":6.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12627456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550178","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":"Pannexin 1 induces Rhabdomyosarcoma cell fusion by downregulating APOBEC2.","authors":"Alexandra Welten, Amit Bera, Stéphanie Langlois, Xiao Xiang, Keshav Gupta, Emily Freeman, Kyle N Cowan","doi":"10.1038/s41389-025-00586-x","DOIUrl":"10.1038/s41389-025-00586-x","url":null,"abstract":"<p><p>Rhabdomyosarcoma (RMS) is an aggressive cancer thought to arise from impaired myogenesis. This can be substantially overcome by increasing the levels of pannexin 1 (PANX1), a critical component of the myogenic program, but the mechanism involved is unknown. Using RNA-seq, we have previously found that overexpression of PANX1 dramatically reshapes the transcriptomic landscape of RMS including downregulation of a myogenic modulator, APOBEC2 (apolipoprotein B mRNA editing enzyme catalytic subunit 2). Following this clue, we investigated the role of APOBEC2 in the PANX1-mediated suppression of RMS malignancy. Here we show that, using a panel of patient-derived RMS cell lines and tumor specimens, APOBEC2 is expressed in RMS, but that its levels are lower than those in both differentiating myoblasts and skeletal muscle. In most RMS cell lines examined, APOBEC2 accumulates during proliferation and sustains their stem-like characteristics, as evidenced by its ability to promote the growth of spheroids upon increased expression. Yet, ectopic PANX1 expression led to a marked downregulation of APOBEC2 across a large proportion of RMS cell lines assessed. Strikingly, these were the same cells in which PANX1 triggers multinucleation. We further reveal that, like healthy myoblasts progressing through myogenesis, the multinucleation observed here in RMS cells results from cell fusion. Importantly, in RMS cells engineered to overexpress APOBEC2, PANX1 no longer enhances cell fusion, but its other anti-tumorigenic properties are still preserved. Collectively, our data indicate that PANX1 promotes RMS cell fusion by downregulating APOBEC2 expression, driving these tumor cells further into the myogenic program.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"43"},"PeriodicalIF":6.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12627423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145550144","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":"YTHDF3 promotes breast cancer osteolytic bone metastasis by enhancing the translation of ZEB1 and SMAD5.","authors":"Lun Xu, Qian Yu, Xu Peihang, Kun Li, Bingnan Wang, Yang Shao, Mo Cheng, Wending Huang, Qianlan Yao, Xu Feng, Shaoli Song, Shuoer Wang, Wangjun Yan","doi":"10.1038/s41389-025-00583-0","DOIUrl":"10.1038/s41389-025-00583-0","url":null,"abstract":"<p><p>Bone metastsis in advanced breast cancer patients are usually osteolytic. A better understanding of the mechanisms in osteolytic metastasis is critical for the development of new therapies. YTH domain-containing family protein 3 (YTHDF3) has been reported to function as an N6-methyladenosine (m6A)-modified mRNA regulator. In this study, we found YTDHF3 expression was associated with clinical characteristics of breast cancer patients. YTHDF3 expression influenced the migration and invasion capacity of breast cancer cells in vitro and in vivo, and low expression of YTHDF3 suppressed cancer cell-induced osteoclast differentiation and osteolytic bone destruction. Moreover, we found YTHDF3 enhanced the translation of zinc finger E-box-binding protein 1 (ZEB1) and SMAD family member 5 (SMAD5) by reading the m6A modification sites in their mRNAs and further promoted the epithelial-mesenchymal transition (EMT) of breast cancer cells. Enhanced expression of ZEB1 promoted the transcription of bone morphogenetic protein inhibitors such as NOG, FST and CCN2, which boosts osteolytic metastasis. Furthermore, we newly found Wnt family member 5B (WNT5B) expression was regulated by ZEB1, also involved in osteolytic process. In conclusion, YTHDF3 plays an important role in osteolytic metastasis and it may serve as a potential prognostic biomarker and therapeutic target for breast cancer bone metastasis.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"41"},"PeriodicalIF":6.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12623997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541551","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":"CMKLR1/PKA signaling reinforces sonic hedgehog pathway to promote medulloblastoma pathogenesis.","authors":"Shan Wang, Tongtong Jiang, Tao Wang, Zhiwei Yang, Ting Wang, Xiao Zhang, Xingchun Gou, Lintao Jia, Liang Wang, Yang Song","doi":"10.1038/s41389-025-00582-1","DOIUrl":"10.1038/s41389-025-00582-1","url":null,"abstract":"<p><p>Aberrant Hedgehog signaling is a key driver of malignancies like medulloblastoma (MB), the most common pediatric brain tumor originating from cerebellar granule neuron progenitors with largely uncharacterized mechanisms. We found here that the G protein-coupled receptor, chemokine-like receptor 1 (CMKLR1), is upregulated and correlates with the development of Sonic Hedgehog (SHH)-subtype MB. SHH and the downstream transcription factor Gli2 license the expression of CMKLR1, which promotes the growth and migration of cells by activating Gα(i)βγ and subsequently the PI3K/Akt signal pathway. SHH/Gli also transcriptionally represses Regulator of G Protein Signaling 16 (RGS16), a known suppressor of Gα(i). Meanwhile, CMKLR1/Gα(i) signaling inactivates protein kinase A (PKA), reduces PKA-catalyzed phosphorylation of Gli2, and circumvents its proteasomal degradation, thus forming a feedback circuit in medulloblastoma cells. Consistently, CMKLR1 ablation suppresses the in vivo development of SHH subtype MB, which is counteracted by further silencing of the PKA catalytic subunit. These findings provide novel insights into the oncogenic network of Hedgehog pathway-driven cancer.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"40"},"PeriodicalIF":6.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12624127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541560","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":"SLC6A19-mediated tryptophan uptake suppresses renal cell carcinoma metastasis via activating NAD⁺-dependent deacetylase SIRT1.","authors":"Ziyi Chen, Runjie Duan, Zeqing Chen, Xinpei Tang, Wenjin Yang, Hongjun Yin, Yijing Chen, Yiqi Cao, Hongqian Guo, Meng Ding, Changwei Ji","doi":"10.1038/s41389-025-00580-3","DOIUrl":"10.1038/s41389-025-00580-3","url":null,"abstract":"<p><p>Metastasis is the hallmark of lethal renal cell carcinoma (RCC), and the underlying mechanism driving RCC metastasis remains insufficiently understood. Amino acid metabolism remodeling plays a key role in the matastasis of RCC. In this study, we identified SLC6A19, a tryptophan transporter, as a novel suppressor gene of RCC, which is closely correlated with the metastasis and survival of RCC patients. Overexpression of SLC6A19 significantly inhibits RCC cell proliferation, migration and invasion both in vitro and in vivo. Mechanistically, SLC6A19 actively transports tryptophan into cells, facilitating de novo NAD⁺ biosynthesis, which in turn activates the NAD⁺-dependent deacetylase SIRT1. This activation drives the deacetylation of histone H3 at lysine 27 (H3K27), thereby restraining the transcription of NF-κB subunit p65, and effectively suppressing the epithelial-mesenchymal transition (EMT) of RCC cells. What's more, the inactivation of the transcription factor KLF4 is the key factor for the low expression of SLC6A19 in RCC cells. In conclusion, this study uncovers a novel key pathway that drives RCC invasion and metastasis, offering a promising therapeutic target for clinical intervention.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"38"},"PeriodicalIF":6.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12595055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471633","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":"NFATc1-mediated activation of the pentose phosphate pathway and cell cycle dysregulation collectively drive tumor progression.","authors":"Suyang Zhang, Guangyao Xu, Tianyu Cao, Fei Yu, Moses Okotel, Mingyue Wu, Shourong Wu, Vivi Kasim, Can Huang","doi":"10.1038/s41389-025-00581-2","DOIUrl":"10.1038/s41389-025-00581-2","url":null,"abstract":"<p><p>The pentose phosphate pathway (PPP) supplies abundant reducing equivalents and biosynthetic precursors to support the rapid proliferation of tumor cells. An increased PPP flux is a hallmark of metabolic reprogramming in tumors. Although nuclear factor of activated T-cells c1 (NFATc1) promotes oncogenesis in various cancers, its role in metabolic reprogramming remains unclear. Here, we demonstrate that NFATc1 enhances NAD kinase (NADK) expression, elevating intracellular NADP⁺ levels to activate the PPP, thereby boosting proliferation. Furthermore, NFATc1 binds to both the p1 and p2 promoters of MDM2, sustaining its expression, thereby promoting metabolic reprogramming and accelerating cell cycle progression. Finally, we demonstrated that NFATc1 inhibitors suppress colorectal cancer (CRC) growth by targeting the NFATc1/NADK and NFATc1/MDM2 axis and synergize with oxaliplatin. In summary, our findings reveal that targeting NFATc1 simultaneously restricts biosynthetic precursors and impairs cell cycle progression in CRC, suggesting that NFATc1 inhibition is a promising therapeutic strategy.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"39"},"PeriodicalIF":6.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12594948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471648","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":"Editorial Expression of Concern: Overexpression of miR-26a-2 in human liposarcoma is correlated with poor patient survival.","authors":"D H Lee, S Amanat, C Goff, L M Weiss, J W Said, N B Doan, A Sato-Otsubo, S Ogawa, C Forscher, H P Koeffler","doi":"10.1038/s41389-025-00584-z","DOIUrl":"10.1038/s41389-025-00584-z","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"37"},"PeriodicalIF":6.4,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12521362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145293062","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":"Non canonical BRCA1 promotes cell survival via modulating PARP13-mediated SEC61G mRNA decay.","authors":"Binghe Sun, Yuting Li, Yue Wu, Cong Wang, Jiawei Zhu, Wanying Zhang, Dake Li, Wancai Que, Guo Chen","doi":"10.1038/s41389-025-00578-x","DOIUrl":"10.1038/s41389-025-00578-x","url":null,"abstract":"<p><p>BRCA1, a well-known tumor suppressor, maintains genomic integrity by facilitating homologous recombination (HR) repair and protecting DNA replication forks. However, its roles beyond DNA repair and replication remain largely unexplored. Here, we demonstrate that BRCA1 interacts with the RNA-binding protein PARP13 in the cytoplasm of ovarian cancer cells, with DNA damage enhancing this interaction via DNA-PK. Notably, BRCA1/PARP13 association is essential for cell survival but does not influence DNA repair efficacy following DNA damage. Mechanistically, PARP13 binds and destabilizes the mRNA of the endoplasmic reticulum (ER) membrane protein SEC61G. Upon DNA damage, BRCA1 disrupts PARP13-mediated SEC61G mRNA decay, leading to SEC61G upregulation. Elevated SEC61G levels cause calcium leakage from the ER into the cytosol, activating the pro-survival kinase Akt. These findings identify the BRCA1-PARP13-SEC61G axis as a non-canonical DNA damage response (DDR) pathway and highlight mRNA stability and ER calcium signaling as potential therapeutic targets to overcome chemoresistance. The schematic illustrates the mechanism by which non-canonical BRCA1 promotes cell survival through regulating PARP13-mediated SEC61G mRNA decay. Under DNA damage-free conditions (left panel), SEC61G maintains cellular calcium homeostasis between the endoplasmic reticulum and cytosol to support normal physiological functions. Upon DNA damage induction (right panel), enhanced interaction between BRCA1 and PARP13 attenuates the mRNA degradation activity of PARP13 toward SEC61G, leading to upregulated SEC61G protein expression. The aberrant accumulation of SEC61G triggers endoplasmic reticulum calcium leakage, which subsequently activates the AKT signaling pathway to enhance cell survival capacity.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"35"},"PeriodicalIF":6.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239283","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":"Investigation of lncRNA expression in newly diagnosed multiple myeloma reveals a LINC01432-CELF2 axis as an inhibitor of apoptosis.","authors":"Richa Mishra, Prasanth Thunuguntla, Dhanusha Duraiyan, Alani Perkin, Katelyn Bagwill, Savannah Gonzales, Catheryn Sizemore, Vanessa Brizuela, Jaiyana King, Stephen Daly, Yoon Jae Chang, Mahdote Abebe, Yash Rajana, Kelly Wichmann, Christ Enyan, Shruthi Rangineni, Mark Fiala, Julie Fortier, Reyka Jayasinghe, Mark Schroeder, Li Ding, Ravi Vij, John DiPersio, Jessica Silva-Fisher","doi":"10.1038/s41389-025-00579-w","DOIUrl":"10.1038/s41389-025-00579-w","url":null,"abstract":"<p><p>Multiple myeloma (MM) is an incurable malignancy of plasma cells, with over 35,000 new cases diagnosed annually in the United States. Despite an expanding arsenal of approved therapies, nearly all patients relapse, and mechanisms underlying disease progression remain poorly understood. In particular, the role of long non-coding RNAs (lncRNAs) in MM progression and treatment response is largely unexplored. To address this gap, we performed transcriptome sequencing of newly diagnosed MM (NDMM) patient samples and compared individuals with short progression-free survival (PFS; <24 months) to those with prolonged PFS (>24 months) following standard first-line therapy. We identified 157 lncRNAs upregulated in patients with short PFS, and prioritized the most significantly upregulated transcript, LINC01432, for functional characterization. CRISPR-mediated knockdown of LINC01432 expression results in upregulation of genes associated with interferon-α/γ responses and increases apoptosis. Targeting LINC01432 with locked nucleic acid antisense oligonucleotides also induces apoptosis, which can be rescued by LINC01432 overexpression. Mechanistically, we discovered that LINC01432 binds the RNA-binding protein CELF2 directly. Transcriptomic analysis following depletion of either LINC01432 or CELF2 revealed 108 overlapping target genes, indicating that this lncRNA-protein complex regulates transcriptional programs governing immune activation, stress response, and cell survival. In summary, this study identified lncRNAs associated with NDMM and characterized LINC01432 as a critical regulator of MM cell survival, acting in complex with CELF2 to repress pro-apoptotic and immune response pathways. These findings highlight LINC01432 as a potential therapeutic target for overcoming resistance in MM.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"36"},"PeriodicalIF":6.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239313","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":"GlycoRNAs are abundant in glioma and involved in glioma cell proliferation.","authors":"Benkai Xin, Jiajun Chen, Xin Hu, Jingtong Yang, Xiaoyu Wang, Ziqian Wang, Youzhong Wan, Lin Wang","doi":"10.1038/s41389-025-00570-5","DOIUrl":"10.1038/s41389-025-00570-5","url":null,"abstract":"<p><p>Recent studies have identified glycosylated RNAs (glycoRNAs) as a novel class of biomolecules potentially involved in cancers and immunological diseases. However, their presence and functional roles in glioma remain unexplored. GlycoRNAs were extracted from glioma cells and detected using Ac4ManNAz labeling and Northern blot. Small RNA deep sequencing and qRT-PCR were employed to determine RNA types and content. A sequence-specific RNA-capture magnetic bead system was developed to enrich specific glycoRNAs, such as U2 and U4. Glycan components were analyzed using liquid chromatography-mass spectrometry. CCK-8, adhesion, ki67, TUNEL staining assays were used to evaluate cell viability, adhesion, proliferation and apoptosis. Glioma cells were found to be rich in glycoRNAs, predominantly small RNAs, with U2 and U4 being particularly abundant. These glycoRNAs primarily contained fucosylated and sialylated complex glycans. The depletion of cell-surface glycoRNAs at the observed time point significantly inhibited glioma cell viability and proliferation, without altering cell adhesion or apoptosis levels. This study underscored the significant role of glycoRNAs in glioma proliferation and provided a foundation for further research into their potential as novel biomarkers and therapeutic targets for glioma. Glioma cells U87 and LN229 showed significant enrichment in glycoRNAs, predominantly small RNAs, with U2 and U4 being particularly abundant and specific. Furthermore, these glycoRNAs were found to be modified by multiple glycans, primarily complex, fucosylated, and sialylated structures.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"29"},"PeriodicalIF":6.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145200520","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}