Oncogenesis最新文献

{"title":"GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells.","authors":"Le Zhang, Lidia Atencia Taboada, Selami Baglamis, Maartje de Kroon, Carolien Elshout, Prashanthi Ramesh, Roxan F C P A Helderman, Arezo Torang, Kate Cameron, Milou S van Driel, Valérie M Wouters, Sanne M van Neerven, Jan Paul Medema","doi":"10.1038/s41389-025-00569-y","DOIUrl":"10.1038/s41389-025-00569-y","url":null,"abstract":"<p><p>BCL-XL is a crucial anti-apoptotic protein that supports survival of intestinal cells during the progression and in established colorectal cancer (CRC). While targeting BCL-XL with BH3 mimetics is effective, its significant toxicity highlights the need for alternative approaches. Importantly, the early steps in intestinal transformation are marked by a competition between normal and transformed stem cells in which the mutant cells gain a supercompetitive advantage due to the secretion of WNT inhibitors. Using multiple human and murine CRC models, we revealed that GSK-3 inhibition strongly sensitized to BH3 mimetic-induced killing. As expected, GSK-3 inhibition significantly upregulated the WNT pathway, but also led to marked enhancement of BH3 mimetic-induced apoptosis, as measured by mitochondrial BAX aggregation, Caspase-3 activation and Propidium Iodide exclusion. Furthermore, GSK-3 inhibition provided an advantage to wild-type intestinal organoids in competition with APC-mutant counterparts due to reactivation of the WNT pathway. More strikingly, combining GSK-3 and BCL-XL inhibition profoundly affected the supercompetition APC-mutant intestinal cells exert over the wild-types. In effect, the combination therapy enhanced the competitive fitness of wild-type cells and resulted in the killing of APC-mutant organoids, pointing to a novel combination therapy that can be further exploited in the treatment of adenomas and CRC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"25"},"PeriodicalIF":5.9,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619705","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":"Ketone drink enhances therapeutic efficacy in prostate cancer by targeting EZH2.","authors":"Chaehyun Yum, Richard A Schaefer, Rui Wang, Ting-You Wang, Xiaotong Lu, Qi Liu, Yanan Ren, Qingshu Meng, Yongyong Yang, Xin Zhang, Yan Xiong, Xufen Yu, Xiaoyu Zhang, Jian Jin, Xuesen Dong, Yang Yi, Rendong Yang, Qi Cao","doi":"10.1038/s41389-025-00567-0","DOIUrl":"10.1038/s41389-025-00567-0","url":null,"abstract":"<p><p>It is well established that EZH2, a lysine methyltransferase, is upregulated in most aggressive cancers, highlighting the importance of EZH2 in cancer progression. Recent research has shown that metabolic reprogramming is pivotal in various biological processes, including cancer. Despite this, evidence of EZH2's role in regulating cancer metabolism remains limited. Our study reveals a negative correlation between EZH2 and HMGCS2, a gene belonging to the HMG-CoA synthase, in prostate and breast cancers. Interestingly, HMGCS2 is inversely related to cancer progression and prognosis in these cancers. Furthermore, HMGCS2 is epigenetically repressed by EZH2 both in vitro and in vivo. Notably, restored EZH2 reduces the elevated HMGCS2 levels observed upon EZH2 depletion. Overexpression of HMGCS2 decreases tumorigenesis in both prostate and breast cancers. Additionally, β-hydroxybutyrate (BHB), a downstream metabolite of HMGCS2, impedes prostate cancer progression by targeting EZH2 via direct protein-compound interaction-mediated protein degradation. More importantly, the ketone drink of BHB administration dramatically reduces tumor size and weight in a therapy-resistant, castration-resistant prostate cancer patient-derived xenograft model. Combining a ketone drink with FDA-approved drugs enzalutamide and Tazemetostat further suppresses tumor progression. Overall, the EZH2-HMGCS2-BHB regulatory network plays a critical role in the progression of prostate cancer, and a ketone drink is a novel therapeutic tool for patients with aggressive prostate cancer.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"24"},"PeriodicalIF":5.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619706","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":"Collagen type IV alpha 6 promotes tumor progression and chemoresistance in ovarian cancer by activating the discoidin domain receptor 1 pathway.","authors":"Yi-Hui Wu, Pei-Ying Wu, Yu-Fang Huang, Chien-Chin Chen, Soon-Cen Huang, Chou Cheng-Yang","doi":"10.1038/s41389-025-00565-2","DOIUrl":"10.1038/s41389-025-00565-2","url":null,"abstract":"<p><p>Biomarkers that predict disease progression may assist in the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. This study aimed to investigate the role of collagen type IV alpha 6 (COL4A6) in cell invasiveness, tumor formation, chemoresistance, and the prognostic impact of COL4A6 expression in ovarian cancer. COL4A6 regulated discoidin domain receptor 1 (DDR1)/p-DDR1 expression through the binding of E2F transcription factor 1 (E2F) to its putative DDR1 promoter binding site, suggesting that the E2F-DDR1 axis is upregulated by COL4A6. Pharmacological inhibition of DDR1 abrogated COL4A6-dependent cell invasiveness and chemoresistance. COL4A6 regulated cell invasion via the E2F1/DDR1/focal adhesion kinase axis; in contrast, COL4A6 regulated cell sensitivity to cisplatin via the DDR1/nuclear factor-kappa B axis. DDR1-IN-1 increased cell sensitivity to cisplatin, synergized with cisplatin to suppress the invasive ability and oncogenic potential of ovarian cancer cells, and decreased tumor formation in mouse xenografts. High COL4A6 mRNA levels were associated with advanced disease stages and poor chemotherapy response. The 5-year recurrence-free and overall survival rates were significantly lower in patients with high tissue COL4A6 mRNA expression levels than in those with low expression levels. COL4A6 may promote tumor aggressiveness and chemoresistance via the E2F/DDR1 axis, and COL4A6 expression can predict clinical outcomes in patients with ovarian cancer. DDR1 should be targeted in patients with COL4A6-positive tumors.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"23"},"PeriodicalIF":5.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554058","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":"Lipid droplet-associated hydrolase (LDAH) knockdown enhances TAG hydrolysis and promotes ovarian cancer progression and chemoresistance.","authors":"Bhawna Deswal, Sameera Nallanthighal, Elahe Nikpayam, Zenab Minhas, Antoni Paul, Young-Hwa Goo, Dong-Joo Cheon","doi":"10.1038/s41389-025-00566-1","DOIUrl":"10.1038/s41389-025-00566-1","url":null,"abstract":"<p><p>Lipid droplet-associated hydrolase (LDAH) is a lipid hydrolase abundantly expressed in adipose and ovarian tissues and macrophages. However, LDAH's functions in ovarian cancer are largely unknown. Analysis of publicly available patient datasets showed decreased LDAH expression in advanced stages of ovarian cancer, and low LDAH levels were associated with poor survival outcomes in ovarian cancer patients. Consistently, knockdown (KD) of LDAH in human ovarian cancer cell lines increased tumor cell proliferation but decreased endoplasmic reticulum (ER) stress and apoptosis upon cisplatin treatment. In addition, compared to scrambled control, LDAH KD ovarian cancer cells showed smaller lipid droplets (LDs), decreased triacylglycerol (TAG) content, and increased expression of adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1 A (CPT1A), and phospho-NF-kB. Our xenograft studies also showed increased tumor growth, increased ATGL expression, and decreased apoptosis after cisplatin treatment in LDAH KD tumors. ATGL overexpression increased cisplatin resistance and expression of CPT1A and phospho-NF-kB, whereas treatment of LDAH KD cells with an ATGL inhibitor attenuated the phenotype. Lastly, we observed that high ATGL levels were associated with shorter survival in ovarian cancer patients. Collectively, our results suggest that ovarian cancer cells downregulate LDAH expression, leading to enhanced ATGL-mediated TAG hydrolysis and increased tumor growth and chemoresistance.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"22"},"PeriodicalIF":5.9,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554073","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":"CD147-high extracellular vesicles promote gastric cancer metastasis via VEGF/AKT/eNOS and AKT/mTOR pathways.","authors":"Chen-Li Zhang, Chan-Yuan Zhao, Jia-Ming Dong, Cun-Pu Du, Bin-Sheng Wang, Chen-Yu Wang, Wei Liu, Yu-Ping Wang, Xiao-Yu Zhang, Quan Zhou, Wei Cai, Yun Dang, Li-Na Shang, Ai-Jun Yang, Min Wang, Min Li","doi":"10.1038/s41389-025-00564-3","DOIUrl":"10.1038/s41389-025-00564-3","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) play a pivotal role in intercellular communication and are closely linked to cancer progression and metastasis. Our previous studies have shown that gastric cancer cell-derived EVs can promote tumor metastasis by increasing the permeability of the endothelial barrier. However, it remains unclear which effector molecule in the EV structure is the key factor of EV-mediated tumor metastasis and the underlying molecular mechanism. In this study, we found that CD147 is a key molecule highly expressed in gastric cancer-derived EVs and confirmed the role of CD147-high EVs from gastric cancer cells in promoting endothelial dysfunction and tumor metastasis. Our results showed that CD147-high EVs activated the VEGF/AKT/eNOS/NO and AKT/mTOR/p70S6K signaling pathways, leading to endothelial cytoskeletal reorganization and internalization of VE-cadherin, which significantly compromised endothelial barrier integrity, increased vascular leakage, enhanced transendothelial migration of tumor cell, and promoted the formation of metastatic tumors. Furthermore, detection of CD147 levels in gastric cancer tissues and plasma EVs indicated that high CD147 expression was associated with advanced tumor stage, poor prognosis, and reduced survival. Our findings suggest that CD147-high EVs are critical mediators of tumor-endothelial interactions and potential diagnostic and prognostic biomarkers for gastric cancer. Their potential as therapeutic targets for gastric cancer is underscored. This figure illustrates the proposed mechanism by which CD147-high gcEVs promote tumor metastasis. CD147-high EVs are released from gastric cancer cells and interact with endothelial cells in the tumor microenvironment. Upon uptake by endothelial cells, CD147-high gcEVs activate the key signaling pathways, including the VEGF/AKT/eNOS/NO and AKT/mTOR/p70S6K pathway, which collectively facilitate the metastatic potential of gastric cancer cells by promoting endothelial cell dysfunction and increasing vascular permeability.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"21"},"PeriodicalIF":5.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336792","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":"ONC201 enhances the cytotoxic effect of cisplatin through ATF3/ATF4/CHOP in head and neck squamous cell carcinoma cells.","authors":"Hui-Ching Chuang, Ming-Hsien Tsai, Jiin-Haur Chuang, Ya-Ting Hong, Chih-Yen Chien, Ming-Huei Chou","doi":"10.1038/s41389-025-00563-4","DOIUrl":"10.1038/s41389-025-00563-4","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) remains a prevalent and challenging cancer to treat due to its genetic heterogeneity. Cisplatin resistance is one of important causes in treatment failure of locally advanced HNSCC. ONC201, a selective dopamine receptor D2 antagonist and mitochondrial ClpP agonist, has emerged as a potential antitumor agent in various malignancies. This study explores the therapeutic potential of ONC201, alone and in combination with cisplatin, in both cisplatin-sensitive and -resistant HNSCC cells, with an emphasis on endoplasmic reticulum (ER) stress-mediated apoptosis. A cisplatin-resistant HNSCC subline (OC2-CR1) was developed via long-term drug exposure. The treatment effectiveness of ONC201 alone and cisplatin in combination on cell viability, DNA damage, reactive oxygen species (ROS) production, and stress response markers were evaluated. ONC201 exhibited potent cytotoxicity in both cisplatin-sensitive and -resistant HNSCC cells, retaining efficacy in OC2-CR1 cells. Combined treatment with ONC201 and cisplatin demonstrated synergistic inhibition of proliferation and migration, with enhanced induction of apoptosis. Mechanistically, ONC201 induced ER stress-mediated cell death via ATF4/CHOP signaling in cisplatin-sensitive cells, while ATF3/CHOP predominated in resistant cells. In vivo, combination therapy significantly suppressed tumor growth in xenograft models, including cisplatin-resistant tumors, without inducing toxicity. Immunohistochemical analysis confirmed activation of CHOP in tumor tissues. Furthermore, clinical correlation revealed that low CHOP expression in OSCC patients was associated with increased recurrence risk and inferior recurrence-free survival significantly. This study provides compelling evidence that ONC201 enhances cisplatin efficacy through distinct, stress-mediated apoptotic pathways in HNSCC. The ability of ONC201 to overcome cisplatin resistance and its synergistic antitumor effects highlight its promise as a candidate for combination therapy. These findings support the translational potential of targeting the ATF3/ATF4/CHOP axis to improve outcomes in patients with cisplatin resistant HNSCC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"20"},"PeriodicalIF":5.9,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326458","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":"NUCKS1 promotes invasion and metastasis of colorectal cancer by stabilizing HDAC2 and activating AKT.","authors":"Liaoliao Zhu, Ting Zhao, Haichuan Su, Junqiang Li, Xiangjing Shen, Liang Zhang, Jun Chen, Yang Song","doi":"10.1038/s41389-025-00562-5","DOIUrl":"10.1038/s41389-025-00562-5","url":null,"abstract":"<p><p>Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) functions as an oncogene in colorectal cancer (CRC), promotes the progression of CRC, and is associated with poor prognosis in patients. Studies have found that NUCKS1 promotes tumor cell metastasis, yet its role in CRC invasion and metastasis remains unclear. Our findings revealed higher NUCKS1 expression in metastatic CRC compared to non-metastatic samples. Upregulation of NUCKS1 expression promoted the migration and invasion of CRC cells, while knockdown of NUCKS1 significantly inhibited the migration and invasion of CRC cells. Mechanistically, NUCKS1 was initially found to upregulate HDAC2 expression by inhibiting the lysosomal pathway, activating AKT, and thus promoting CRC invasion and metastasis. Moreover, HDAC2 inhibitor Santacruzamate A or AKT inhibitor LY294002 rescued the migration and invasion of CRC cells caused by NUCKS1 overexpression. In vivo, by injecting CRC cells into the tail vein of a nude mouse model, we found that overexpression of NUCKS1-induced lung and liver metastasis was suppressed by HDAC2 knockdown or intraperitoneal administration of the HDAC2 inhibitor Santacruzamate A. Meanwhile, AKT inhibitor LY294002 significantly inhibited lung and liver metastasis caused by overexpression of HDAC2. The expression levels of NUCKS1, HDAC2, and phosphorylated AKT were significantly positively correlated in human CRC tissues. These findings suggest that NUCKS1 contributes to CRC invasion and metastasis by stabilizing HDAC2 and activating AKT, highlighting NUCKS1 and HDAC2 as potential therapeutic targets for CRC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"19"},"PeriodicalIF":5.9,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317546","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":"Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma.","authors":"Shunpei Satoh, Mariko Hasegawa, Ryu Okada, Masayuki Haruta, Hisanori Takenobu, Miki Ohira, Takehiko Kamijo","doi":"10.1038/s41389-025-00561-6","DOIUrl":"10.1038/s41389-025-00561-6","url":null,"abstract":"<p><p>Cancer cells exploit epigenetic modifications and post-transcriptional regulations to form oncogenic gene expression networks. However, how these machineries collaboratively orchestrate malignancy remains elusive. One of aberrant epigenetic pathways in cancer is Polycomb repressive complex 1 (PRC)-mediated H2AK119 monoubiquitination (H2AK119ub1) with subsequent silencing of tumor suppressor genes. Despite previous efforts, the biological and clinical significance of PRC1 remains unclear in neuroblastoma (NB), an aggressive sympathoadrenal solid tumor in children. In this study, we demonstrated that knockdown of RING1A, one of the E3 ubiquitin ligases of PRC1, reduced cell viability and enrichment of H2AK119ub1 in NB cells. Transcriptional profiling revealed RING1A-specific targets, whose lower expression was associated with poor outcomes in NB patients. Among these genes, BTG2, a component of the CCR4-NOT polyA deadenylase complex, harbored a hypomethylated CpG island occupied by H2AK119ub1 and accessory proteins of noncanonical PRC1.1 (ncPRC1.1). Biological experiments uncovered that BTG2 suppressed NB cell growth in vitro and inhibited tumor formation in vivo. Moreover, BTG2 perturbed cell cycle progression and selectively destabilized the mRNAs of the cyclin genes CCNA2, CCNB1, and CCNB2. In NB patient cohorts, lower expression of BTG2 was associated with poor outcomes and inversely correlated with those cyclin gene expression. Collectively, we have uncovered a crosstalk between epigenetic modifications and post-transcriptional regulations, in which ncPRC1.1-mediated silencing of BTG2 retains cyclin gene expression and cell proliferation in NB. This study provides new insights into how epigenetic pathways contribute to NB malignancy.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"18"},"PeriodicalIF":5.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216486","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":"TGF-β signaling redirects Sox11 gene regulatory activity to promote partial EMT and collective invasion of oncogenically transformed intestinal organoids.","authors":"Yu-Hsiang Teng, Bismark Appiah, Geoffroy Andrieux, Monika Schrempp, Katja Rose, Angelika Susanna Hofmann, Manching Ku, Sven Beyes, Melanie Boerries, Andreas Hecht","doi":"10.1038/s41389-025-00560-7","DOIUrl":"10.1038/s41389-025-00560-7","url":null,"abstract":"<p><p>Cancer cells infiltrating surrounding tissue frequently undergo partial epithelial-mesenchymal transitions (pEMT) and employ a collective mode of invasion. How these phenotypic traits are regulated and interconnected remains underexplored. Here, we used intestinal organoids with colorectal cancer (CRC) driver mutations as model system to investigate the mechanistic basis of TGF-β1-induced pEMT and collective invasion. By scRNA-seq we identified multiple cell subpopulations representing a broad pEMT spectrum, where the most advanced pEMT state correlated with the transcriptional profiles of leader cells in collective invasion and a poor prognosis mesenchymal subtype of human CRC. Bioinformatic analyses pinpointed Sox11 as a transcription factor gene whose expression peaked in the potential leader/pEMT^high cells. Immunofluorescence staining confirmed Sox11 expression in cells at the invasive front of TGF-β1-treated organoids. Loss-of-function and overexpression experiments showed that Sox11 is necessary, albeit not sufficient, for TGF-β1-induced pEMT and collective invasion. In human CRC samples, elevated SOX11 expression was associated with advanced tumor stages and worse prognosis. Unexpectedly, aside from orchestrating the organoid response to TGF-β1, Sox11 controlled expression of genes related to normal gut function and tumor suppression. Apparently, Sox11 is embedded in several distinct gene regulatory circuits, contributing to intestinal tissue homeostasis, tumor suppression, and TGF-β-mediated cancer cell invasion.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"17"},"PeriodicalIF":5.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111430","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":"SYT7 accelerates nasopharyngeal carcinoma progression via ALDH1A3-mediated STAT3 signaling activation.","authors":"Kai Xu, Yifan Kang, Jing Wang, Ying Hou, Wenxiang Zheng, Wenxiu Tian, Chuanjie Liang, Yongliang Liu, Xinxin Xiang","doi":"10.1038/s41389-025-00558-1","DOIUrl":"https://doi.org/10.1038/s41389-025-00558-1","url":null,"abstract":"<p><p>Nasopharyngeal carcinoma (NPC) is a special histological and ethical type of head and neck cancer with unsatisfactory clinical outcome. Thus, exploring effective molecular targets is critical for NPC treatment. We observed increased expression levels of synaptotagmin-7 (SYT7) in NPC tissues, which correlated with unfavorable prognoses. Furthermore, knockdown of SYT7 in NPC cells suppressed proliferation and migration rates, and enhanced apoptosis. In contrast, overexpression of SYT7 accelerated NPC tumor growth. Using whole-genome gene arrays and immunoprecipitation-mass spectrometry assays, aldehyde dehydrogenase 1 family member A3 (ALDH1A3), a regulator of glycolytic metabolism, was identified as a critical downstream target of SYT7. Mechanistically, SYT7 binds and promotes ALDH1A3 deubiquitination, resulting in decreased ALDH1A3 degradation. Notably, we also observed an increased expression of ALDH1A3 in NPC. More importantly, the knockdown of ALDH1A3 resulted in suppressed proliferation, migration, glycolysis, and promoted apoptosis, all of which could be restored by the overexpression of SYT7 in NPC cells. Taken together, we found that SYT7 increases ALDH1A3-mediated STAT3 activation and glycolysis, contributing to NPC progression, which provides a possible molecular mechanism for the development of targeted therapeutics interventions.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"14 1","pages":"16"},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003778","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}