The clinical application of combination chemotherapy with cisplatin is unsatisfactory for most pancreatic cancer patients with wild-type BRCA1/2 or PALB2 due to resistance. Genes associated with cisplatin resistance in patients without BRCA1/2 or PALB2 mutations should be pursued. Through bioinformatics analysis, we found that Myotrophin (MTPN) expression was correlated with that of nuclear factor kappa B (NF-κB), a protein involved in the regulation of cisplatin sensitivity. Immunohistochemistry revealed that MTPN was more highly expressed in human pancreatic cancer tissues than in normal tissues. MTPN promoted the malignant biological behaviors of pancreatic cancer (PC) cells and activated the epithelial-mesenchymal transition process. Furthermore, MTPN was found to induce cisplatin resistance in PC cells and upregulate BRCA1/2 while promoting DNA repair. The enhancing effects of MTPN on cisplatin resistance and BRCA1/2 up-regulation were abolished by an inhibitor of IκBα phosphorylation. These studies suggested that MTPN may increase cisplatin resistance by activating IκBα to regulate BRCA1/2 expression. In summary, targeting MTPN could be a potential therapeutic strategy, as MTPN knockdown increased the sensitivity to cisplatin-based chemotherapy in pancreatic cancer with wild-type BRCA1/2.
对于野生型BRCA1/2或PALB2的大多数胰腺癌患者，由于耐药，联合顺铂化疗的临床应用并不理想。在没有BRCA1/2或PALB2突变的患者中，与顺铂耐药相关的基因应该被追踪。通过生物信息学分析，我们发现肌营养因子（MTPN）的表达与参与顺铂敏感性调节的核因子κB （NF-κB）的表达相关。免疫组化显示MTPN在人胰腺癌组织中的表达高于正常组织。MTPN促进胰腺癌细胞的恶性生物学行为，激活上皮-间质转化过程。此外，MTPN在PC细胞中诱导顺铂耐药，上调BRCA1/2，同时促进DNA修复。MTPN对顺铂耐药和BRCA1/2上调的增强作用被i - κ b α磷酸化抑制剂所消除。这些研究提示MTPN可能通过激活IκBα调控BRCA1/2表达而增加顺铂耐药。总之，靶向MTPN可能是一种潜在的治疗策略，因为MTPN敲除增加了野生型BRCA1/2胰腺癌患者对顺铂化疗的敏感性。
{"title":"Targeting MTPN sensitizes pancreatic cancer of wild-type BRCA1/2 to Cisplatin-based chemotherapy","authors":"Zhuoxin Wang, Xinyang Huang, Tingting Bai, Yixun Jin, Tingting Gong, Wei Wu, Berik Kouken, Qi Wang, Lifu Wang","doi":"10.1038/s41417-025-00925-5","DOIUrl":"10.1038/s41417-025-00925-5","url":null,"abstract":"The clinical application of combination chemotherapy with cisplatin is unsatisfactory for most pancreatic cancer patients with wild-type BRCA1/2 or PALB2 due to resistance. Genes associated with cisplatin resistance in patients without BRCA1/2 or PALB2 mutations should be pursued. Through bioinformatics analysis, we found that Myotrophin (MTPN) expression was correlated with that of nuclear factor kappa B (NF-κB), a protein involved in the regulation of cisplatin sensitivity. Immunohistochemistry revealed that MTPN was more highly expressed in human pancreatic cancer tissues than in normal tissues. MTPN promoted the malignant biological behaviors of pancreatic cancer (PC) cells and activated the epithelial-mesenchymal transition process. Furthermore, MTPN was found to induce cisplatin resistance in PC cells and upregulate BRCA1/2 while promoting DNA repair. The enhancing effects of MTPN on cisplatin resistance and BRCA1/2 up-regulation were abolished by an inhibitor of IκBα phosphorylation. These studies suggested that MTPN may increase cisplatin resistance by activating IκBα to regulate BRCA1/2 expression. In summary, targeting MTPN could be a potential therapeutic strategy, as MTPN knockdown increased the sensitivity to cisplatin-based chemotherapy in pancreatic cancer with wild-type BRCA1/2.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 11","pages":"1245-1258"},"PeriodicalIF":5.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatocellular carcinoma (HCC) is a common liver cancer often diagnosed at an advanced stage. While chemotherapies such as sorafenib is effective for some patients, others show poor responses, necessitating new treatments. Overexpression of MYCN/NCYM was recently shown to contribute to the development of HCC. This study investigated the effects of Pentagamavunone-1 (PGV-1), a curcumin analog with strong antiproliferative properties, on HCC cells expressing MYCN/NCYM. PGV-1 was more effective than curcumin and sorafenib in inhibiting HCC cell proliferation by inducing mitotic arrest, oxidative stress, and senescence. In MYCN-positive JHH-7 cells, PGV-1 treatment increased phosphorylation of aurora A, cyclin B1, and PLK1. PGV-1 also suppressed MYCN/NCYM transcription and destabilized MYCN protein by inducing phosphorylation at Ser54 and Thr58. In a xenograft model, PGV-1 significantly reduced tumor formation and growth. These findings highlight PGV-1’s potential as a targeted therapy for MYCN-overexpressing HCC, warranting further development.
{"title":"Pentagamavunone-1 targets excessive MYCN/NCYM expression mediated by mitotic arrest to suppress hepatocellular carcinoma proliferation","authors":"Dhania Novitasari, Ikuko Nakamae, Noriko Yoneda-Kato, Edy Meiyanto, Jun-ya Kato","doi":"10.1038/s41417-025-00956-y","DOIUrl":"10.1038/s41417-025-00956-y","url":null,"abstract":"Hepatocellular carcinoma (HCC) is a common liver cancer often diagnosed at an advanced stage. While chemotherapies such as sorafenib is effective for some patients, others show poor responses, necessitating new treatments. Overexpression of MYCN/NCYM was recently shown to contribute to the development of HCC. This study investigated the effects of Pentagamavunone-1 (PGV-1), a curcumin analog with strong antiproliferative properties, on HCC cells expressing MYCN/NCYM. PGV-1 was more effective than curcumin and sorafenib in inhibiting HCC cell proliferation by inducing mitotic arrest, oxidative stress, and senescence. In MYCN-positive JHH-7 cells, PGV-1 treatment increased phosphorylation of aurora A, cyclin B1, and PLK1. PGV-1 also suppressed MYCN/NCYM transcription and destabilized MYCN protein by inducing phosphorylation at Ser54 and Thr58. In a xenograft model, PGV-1 significantly reduced tumor formation and growth. These findings highlight PGV-1’s potential as a targeted therapy for MYCN-overexpressing HCC, warranting further development.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 11","pages":"1233-1244"},"PeriodicalIF":5.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a dismal prognosis. Hitherto, little has been known regarding the clinical implications of tertiary lymphoid structures (TLS) and its biological mechanisms of antitumor effect on treatment-naïve ESCC. We herein identified the presence of TLS as an independent factor for favorable survival. By characterizing the immune infiltration and genomic profiles based on transcriptomic datasets, we found TLS abundant in enriched B cells with IRF4 as a signature gene. Increased expression of IRF4 and its positive correlation with STING in activating tumor-infiltrating B cells were also investigated using a single-cell RNA sequencing dataset. CD40 as a co-regulator of IRF4 and TLS formation, in vitro experiments were conducted to further demonstrate the competitive binding relationships between CD40 and STING with TRAF2 in promoting IRF4 expression and B cell activation via the non-canonical NF-kB signaling pathway, in which CD40 reduced STING ubiquitination while promoting its phosphorylation. Our data provided deeper insights into the potential role of activated B cells and TLS in ESCC, with implications for the development of biomarkers and therapeutic targets.
{"title":"Characterization of tertiary lymphoid structure identifies competitive binding of CD40 and STING with TRAF2 driving IRF4-mediated B cell activation in esophageal squamous cell carcinoma","authors":"Yujia Zheng, Donglai Chen, Yi Xu, Xuejun Xu, Peidong Song, Xuejie Wu, Lijie Tan, Yiming Mao, Yongbing Chen","doi":"10.1038/s41417-025-00944-2","DOIUrl":"10.1038/s41417-025-00944-2","url":null,"abstract":"Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a dismal prognosis. Hitherto, little has been known regarding the clinical implications of tertiary lymphoid structures (TLS) and its biological mechanisms of antitumor effect on treatment-naïve ESCC. We herein identified the presence of TLS as an independent factor for favorable survival. By characterizing the immune infiltration and genomic profiles based on transcriptomic datasets, we found TLS abundant in enriched B cells with IRF4 as a signature gene. Increased expression of IRF4 and its positive correlation with STING in activating tumor-infiltrating B cells were also investigated using a single-cell RNA sequencing dataset. CD40 as a co-regulator of IRF4 and TLS formation, in vitro experiments were conducted to further demonstrate the competitive binding relationships between CD40 and STING with TRAF2 in promoting IRF4 expression and B cell activation via the non-canonical NF-kB signaling pathway, in which CD40 reduced STING ubiquitination while promoting its phosphorylation. Our data provided deeper insights into the potential role of activated B cells and TLS in ESCC, with implications for the development of biomarkers and therapeutic targets.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 11","pages":"1206-1217"},"PeriodicalIF":5.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00944-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatocellular carcinoma (HCC) progression is tightly linked to metabolic reprogramming and immune evasion. However, the transcriptional networks driving these processes remain misunderstood. Here, we identified a novel regulatory axis wherein the transcription factor SOX4 formed a stress-responsive complex with NRF2, as confirmed by co-immunoprecipitation and proximity ligation assay. This process was orchestrated via p62-mediated disruption of the KEAP1–SOX4 complex. The SOX4–NRF2 complex directly activated Phosphoserine Phosphatase (PSPH) transcription—as revealed by luciferase reporter and chromatin immunoprecipitation—enhancing serine biosynthesis and downstream metabolites critical for oxidative phosphorylation (OXPHOS) and redox balance. Inhibition of SOX4 or NRF2 impaired PSPH expression, exacerbated oxidative damage—marked by elevated 4-hydroxynonenal—and increased sensitivity to sorafenib treatment in HCC cells. Furthermore, PSPH-driven metabolites, particularly serine, fostered M2-like macrophage polarization, thereby potentially contributing to the promotion of an immunosuppressive tumor microenvironment. Analysis of HCC specimens from TCGA and clinical cohorts confirmed that high SOX4/NRF2/PSPH expression was correlated with increasing M2 macrophage infiltration and poor patient prognosis. Our findings revealed a previously unrecognized SOX4–NRF2–PSPH regulatory loop that coupled cancer metabolism with immune modulation. Targeting this axis may offer a promising therapeutic avenue to simultaneously disrupt metabolic support and immune evasion in HCC.
{"title":"NRF2-SOX4 complex regulates PSPH in hepatocellular carcinoma and modulates M2 macrophage differentiation","authors":"Chi-Neu Tsai, Ming-Chin Yu, Yun-Shien Lee, Kuan-Chuan Feng, Chun-Hsing Wu, Yi-Chin Li, Mei-Ling Cheng, Sey-En Lin, Song-Fong Huang, Tien-An Lin, Chia-Lung Tsai","doi":"10.1038/s41417-025-00951-3","DOIUrl":"10.1038/s41417-025-00951-3","url":null,"abstract":"Hepatocellular carcinoma (HCC) progression is tightly linked to metabolic reprogramming and immune evasion. However, the transcriptional networks driving these processes remain misunderstood. Here, we identified a novel regulatory axis wherein the transcription factor SOX4 formed a stress-responsive complex with NRF2, as confirmed by co-immunoprecipitation and proximity ligation assay. This process was orchestrated via p62-mediated disruption of the KEAP1–SOX4 complex. The SOX4–NRF2 complex directly activated Phosphoserine Phosphatase (PSPH) transcription—as revealed by luciferase reporter and chromatin immunoprecipitation—enhancing serine biosynthesis and downstream metabolites critical for oxidative phosphorylation (OXPHOS) and redox balance. Inhibition of SOX4 or NRF2 impaired PSPH expression, exacerbated oxidative damage—marked by elevated 4-hydroxynonenal—and increased sensitivity to sorafenib treatment in HCC cells. Furthermore, PSPH-driven metabolites, particularly serine, fostered M2-like macrophage polarization, thereby potentially contributing to the promotion of an immunosuppressive tumor microenvironment. Analysis of HCC specimens from TCGA and clinical cohorts confirmed that high SOX4/NRF2/PSPH expression was correlated with increasing M2 macrophage infiltration and poor patient prognosis. Our findings revealed a previously unrecognized SOX4–NRF2–PSPH regulatory loop that coupled cancer metabolism with immune modulation. Targeting this axis may offer a promising therapeutic avenue to simultaneously disrupt metabolic support and immune evasion in HCC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 11","pages":"1218-1232"},"PeriodicalIF":5.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-23DOI: 10.1038/s41417-025-00954-0
Elisabetta Cozzi, Anne Neddermeyer, Xiangfu Zhong, Angelica María Gamboa-Cedeño, Dimitris C. Kanellis, Albin Österroos, My Björklund, Nona Struyf, Kasper Karlsson, Ying Qu, Alma Månsson, Tatjana Pandzic, Sofia Bengtzén, Christer Nilsson, Roland Fiskesund, Panagiotis Baliakas, Tom Erkers, Jiri Bartek, Olli-Pekka Kallioniemi, Hong Qian, Andreas Lennartsson, Sören Lehmann
As the non-coding genome remains poorly characterized in acute myeloid leukemia (AML), we aimed to identify and functionally characterize novel long non-coding RNAs (lncRNAs) relevant to AML biology and treatment. We first identified lncRNAs overexpressed in AML blasts and, among them, discovered a novel transcript, which we named myeloid and AML-associated intergenic long non-coding RNA (MALNC). MALNC is overexpressed in AML, particularly in cases with the PML-RARA fusion or IDH2R140/NPM1 co-mutations, and is associated with a distinct gene expression profile. Functional studies showed that MALNC knockout impairs AML cell proliferation and colony formation, enhances ATRA-induced differentiation, and sensitizes cells to arsenic trioxide. Transcriptomic analysis revealed that MALNC loss alters the expression of retinoic acid pathway genes, and chromatin binding studies showed that MALNC binds to genes related to the retinoic acid and Rho GTPase pathways. In conclusion, we have identified MALNC as a novel lncRNA that promotes leukemic cell proliferation, counteracts ATRA-induced differentiation, and modulates drug sensitivity in AML.
{"title":"MALNC: a new mutant NPM1/IDH2R140 and PML-RARA-associated lncRNA with impact on AML cell proliferation, maturation and drug response","authors":"Elisabetta Cozzi, Anne Neddermeyer, Xiangfu Zhong, Angelica María Gamboa-Cedeño, Dimitris C. Kanellis, Albin Österroos, My Björklund, Nona Struyf, Kasper Karlsson, Ying Qu, Alma Månsson, Tatjana Pandzic, Sofia Bengtzén, Christer Nilsson, Roland Fiskesund, Panagiotis Baliakas, Tom Erkers, Jiri Bartek, Olli-Pekka Kallioniemi, Hong Qian, Andreas Lennartsson, Sören Lehmann","doi":"10.1038/s41417-025-00954-0","DOIUrl":"10.1038/s41417-025-00954-0","url":null,"abstract":"As the non-coding genome remains poorly characterized in acute myeloid leukemia (AML), we aimed to identify and functionally characterize novel long non-coding RNAs (lncRNAs) relevant to AML biology and treatment. We first identified lncRNAs overexpressed in AML blasts and, among them, discovered a novel transcript, which we named myeloid and AML-associated intergenic long non-coding RNA (MALNC). MALNC is overexpressed in AML, particularly in cases with the PML-RARA fusion or IDH2R140/NPM1 co-mutations, and is associated with a distinct gene expression profile. Functional studies showed that MALNC knockout impairs AML cell proliferation and colony formation, enhances ATRA-induced differentiation, and sensitizes cells to arsenic trioxide. Transcriptomic analysis revealed that MALNC loss alters the expression of retinoic acid pathway genes, and chromatin binding studies showed that MALNC binds to genes related to the retinoic acid and Rho GTPase pathways. In conclusion, we have identified MALNC as a novel lncRNA that promotes leukemic cell proliferation, counteracts ATRA-induced differentiation, and modulates drug sensitivity in AML.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 11","pages":"1191-1205"},"PeriodicalIF":5.0,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00954-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-21DOI: 10.1038/s41417-025-00940-6
Xi Pu, Yuting Wu, Chen Peng, Xinyu Sun, Hao Zuo, Xiao Yuan, Xu Wang, Min Xu
Tumorigenesis is closely related to an imbalance in cell death regulation. PANoptosis is a recently characterized form of programmed cell death that integrates the molecular features of cellular pyroptosis, apoptosis and necrotic apoptosis through the assembly of a multiprotein complex termed the PANoptosome. Beyond its role in cancer initiation and progression, PANoptosis is intricately linked to immune responses within the tumor microenvironment, thus offering new avenues for therapeutic intervention. The present review outlines the interplay among different cell death pathways, highlights the defining characteristics and assembly mechanisms of PANoptosis, as well as discusses its functional roles in cancer biology. Additionally, the implications of PANoptosis in tumor immunity and the potential of targeting this pathway in cancer therapy are explored.
{"title":"PANoptosis in cancer: molecular mechanisms and therapeutic potential","authors":"Xi Pu, Yuting Wu, Chen Peng, Xinyu Sun, Hao Zuo, Xiao Yuan, Xu Wang, Min Xu","doi":"10.1038/s41417-025-00940-6","DOIUrl":"10.1038/s41417-025-00940-6","url":null,"abstract":"Tumorigenesis is closely related to an imbalance in cell death regulation. PANoptosis is a recently characterized form of programmed cell death that integrates the molecular features of cellular pyroptosis, apoptosis and necrotic apoptosis through the assembly of a multiprotein complex termed the PANoptosome. Beyond its role in cancer initiation and progression, PANoptosis is intricately linked to immune responses within the tumor microenvironment, thus offering new avenues for therapeutic intervention. The present review outlines the interplay among different cell death pathways, highlights the defining characteristics and assembly mechanisms of PANoptosis, as well as discusses its functional roles in cancer biology. Additionally, the implications of PANoptosis in tumor immunity and the potential of targeting this pathway in cancer therapy are explored.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1042-1053"},"PeriodicalIF":5.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bladder cancer (BC) is a malignancy that originates from the cells lining the bladder and is one of the most common cancers of the urinary system, capable of occurring in any part of the bladder. However, the molecular mechanisms underlying the malignant transformation of BC have not been systematically studied. This study integrated cutting-edge techniques of spatial transcriptomics (ST) and spatial metabolomics (SM) to capture the transcriptomic and metabolomic landscapes of both BC and adjacent normal tissues. ST results revealed a significant upregulation of genes associated with choline metabolism and glucose metabolism, while genes related to sphingolipid metabolism and tryptophan metabolism were significantly downregulated. Additionally, significant metabolic reprogramming was observed in BC tissues, including the upregulation of choline metabolism and glucose metabolism, as well as the downregulation of sphingolipid metabolism and tryptophan metabolism. These alterations may play a crucial role in promoting tumorigenesis and immune evasion of BC. The interpretation of ST and SM data in this study offers new insights into the molecular mechanisms underlying BC progression and provides valuable clues for the prevention and treatment of BC.
{"title":"Integrated spatial transcriptome and metabolism study reveals metabolic heterogeneity in human bladder cancer","authors":"Yu Lu, Fangdie Ye, Xuedan Han, Zihan Wang, Xiaoman Li, Lufeng Zheng","doi":"10.1038/s41417-025-00947-z","DOIUrl":"10.1038/s41417-025-00947-z","url":null,"abstract":"Bladder cancer (BC) is a malignancy that originates from the cells lining the bladder and is one of the most common cancers of the urinary system, capable of occurring in any part of the bladder. However, the molecular mechanisms underlying the malignant transformation of BC have not been systematically studied. This study integrated cutting-edge techniques of spatial transcriptomics (ST) and spatial metabolomics (SM) to capture the transcriptomic and metabolomic landscapes of both BC and adjacent normal tissues. ST results revealed a significant upregulation of genes associated with choline metabolism and glucose metabolism, while genes related to sphingolipid metabolism and tryptophan metabolism were significantly downregulated. Additionally, significant metabolic reprogramming was observed in BC tissues, including the upregulation of choline metabolism and glucose metabolism, as well as the downregulation of sphingolipid metabolism and tryptophan metabolism. These alterations may play a crucial role in promoting tumorigenesis and immune evasion of BC. The interpretation of ST and SM data in this study offers new insights into the molecular mechanisms underlying BC progression and provides valuable clues for the prevention and treatment of BC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 11","pages":"1177-1190"},"PeriodicalIF":5.0,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-16DOI: 10.1038/s41417-025-00953-1
Nadine Mahmoud, Xingping Qin, Wafaa Bzeih, Damir Khabibullin, Michel Alchoueiry, Steven Safi, Joelle Chami, Tiegang Han, Samer Salem, Carmen Priolo, Abhishek A. Chakraborty, Kristopher A. Sarosiek, Elizabeth P. Henske
Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of kidney cancer, with limited therapeutic options. Using BH3 profiling to screen ChRCC-derived cell lines, we discovered that BH3 peptides targeting BCL-xL promote apoptosis in ChRCC. Downregulation of BCL2L1 is sufficient to induce apoptosis in ChRCC-derived cells, consistent with our screening results. BCL2L1, encoding BCL-xL, is fourfold upregulated in ChRCC compared to normal kidney and has the second highest expression in The Cancer Genome Atlas. BCL2L1 downregulation enhances MCL-1 expression, suggesting a possible compensatory role for MCL-1. Based on these results, we evaluated two BH3 mimetics, A-1331852 (targeting BCL-xL) and S63845 (targeting MCL-1). Their combination resulted in 80% cell death. DT2216, a proteolysis-targeting chimera (PROTAC) that targets BCL-xL for degradation, induced cleaved PARP and caspase 3, indicators of apoptosis. ChRCC cells are known to be highly sensitive to ferroptosis. We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). BCL-xL and MCL-1 inhibition enhanced the susceptibility to ferroptosis, suggesting a link between apoptosis and ferroptosis in ChRCC. These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy.
{"title":"BCL-xL dependency in chromophobe renal cell carcinoma","authors":"Nadine Mahmoud, Xingping Qin, Wafaa Bzeih, Damir Khabibullin, Michel Alchoueiry, Steven Safi, Joelle Chami, Tiegang Han, Samer Salem, Carmen Priolo, Abhishek A. Chakraborty, Kristopher A. Sarosiek, Elizabeth P. Henske","doi":"10.1038/s41417-025-00953-1","DOIUrl":"10.1038/s41417-025-00953-1","url":null,"abstract":"Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of kidney cancer, with limited therapeutic options. Using BH3 profiling to screen ChRCC-derived cell lines, we discovered that BH3 peptides targeting BCL-xL promote apoptosis in ChRCC. Downregulation of BCL2L1 is sufficient to induce apoptosis in ChRCC-derived cells, consistent with our screening results. BCL2L1, encoding BCL-xL, is fourfold upregulated in ChRCC compared to normal kidney and has the second highest expression in The Cancer Genome Atlas. BCL2L1 downregulation enhances MCL-1 expression, suggesting a possible compensatory role for MCL-1. Based on these results, we evaluated two BH3 mimetics, A-1331852 (targeting BCL-xL) and S63845 (targeting MCL-1). Their combination resulted in 80% cell death. DT2216, a proteolysis-targeting chimera (PROTAC) that targets BCL-xL for degradation, induced cleaved PARP and caspase 3, indicators of apoptosis. ChRCC cells are known to be highly sensitive to ferroptosis. We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). BCL-xL and MCL-1 inhibition enhanced the susceptibility to ferroptosis, suggesting a link between apoptosis and ferroptosis in ChRCC. These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1133-1143"},"PeriodicalIF":5.0,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-16DOI: 10.1038/s41417-025-00952-2
Yining Zhang, Jinfa Wu, Jiaming Liu
Long non-coding RNAs (lncRNAs) have attracted significant attention for their role in tumor initiation and progression. Specifically, studying lncRNA small nucleolar RNA host genes (lncSNHGs) has opened up new possibilities for the treatment of osteosarcoma (OS). This review aims to give a thorough overview of the state of research on the biological roles, molecular mechanisms, and expression of the lncRNA SNHG family in OS. Through an extensive analysis, it is demonstrated that members of the SNHG family exhibit dysregulated expression patterns in OS. These dysregulations affect multiple oncogenic processes, including tumor proliferation, metastasis, apoptosis, autophagy, and chemotherapy resistance. The lncRNA SNHG family promises to identify novel strategies and targets for diagnosing, treating, and prognosis OS.
{"title":"LncSNHGs: new targets in osteosarcoma","authors":"Yining Zhang, Jinfa Wu, Jiaming Liu","doi":"10.1038/s41417-025-00952-2","DOIUrl":"10.1038/s41417-025-00952-2","url":null,"abstract":"Long non-coding RNAs (lncRNAs) have attracted significant attention for their role in tumor initiation and progression. Specifically, studying lncRNA small nucleolar RNA host genes (lncSNHGs) has opened up new possibilities for the treatment of osteosarcoma (OS). This review aims to give a thorough overview of the state of research on the biological roles, molecular mechanisms, and expression of the lncRNA SNHG family in OS. Through an extensive analysis, it is demonstrated that members of the SNHG family exhibit dysregulated expression patterns in OS. These dysregulations affect multiple oncogenic processes, including tumor proliferation, metastasis, apoptosis, autophagy, and chemotherapy resistance. The lncRNA SNHG family promises to identify novel strategies and targets for diagnosing, treating, and prognosis OS.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1031-1041"},"PeriodicalIF":5.0,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glioblastoma multiforme (GBM) is an aggressive brain tumor partly driven by cancer stem cells (CSCs). Abemaciclib demonstrates the potential for treating GBM, although its mechanisms beyond RB phosphorylation are not fully understood. This study reveals that Abemaciclib diminishes GBM sphere formation by influencing EMT pathways via GSK3β-mediated regulation of CD44 and TCF7L2. Treatment with Abemaciclib significantly hindered sphere formation in GBM cells, and transcriptomic analysis indicated EMT pathways suppression. Mechanistically, Abemaciclib consistently lowered the expression of CD44 and TCF7L2 in both parental and sphere cells by inhibiting GSK3β phosphorylation. A pharmacological GSK3β inhibitor produced similar effects, reinforcing the existence of a GSK3β-CD44/TCF7L2 axis. Moreover, orthotopic xenografts confirmed reduced tumor growth and CD44 expression in vivo. Analyses of TCGA and CGGA datasets revealed that the mesenchymal GBM subtype (MES-GBM), linked with poor outcomes, exhibits elevated EMT gene expression. Treatment of MES-like LN229 cells with Abemaciclib resulted in decreased phosphorylation of GSK3β and reductions in EMT-related gene expression. Our findings highlight a novel EMT-suppressive action of Abemaciclib, illustrating its therapeutic potential for targeting the CSCs and for treating the MES-GBM. This research provides mechanistic insights and justification for repurposing Abemaciclib as targeted therapies for aggressive glioblastoma.
{"title":"Abemaciclib impairs glioblastoma sphere formation by targeting the GSK3β-mediated transcriptional regulation of CD44 and TCF7L2","authors":"Muh-Lii Liang, Chun-Han Chen, Ya-Ching Lin, Yu-Chen Lin, Yun-Ru Liu, Yi-Huei Ding, Cheng-Ying Chu, Tsung-Han Hsieh","doi":"10.1038/s41417-025-00955-z","DOIUrl":"10.1038/s41417-025-00955-z","url":null,"abstract":"Glioblastoma multiforme (GBM) is an aggressive brain tumor partly driven by cancer stem cells (CSCs). Abemaciclib demonstrates the potential for treating GBM, although its mechanisms beyond RB phosphorylation are not fully understood. This study reveals that Abemaciclib diminishes GBM sphere formation by influencing EMT pathways via GSK3β-mediated regulation of CD44 and TCF7L2. Treatment with Abemaciclib significantly hindered sphere formation in GBM cells, and transcriptomic analysis indicated EMT pathways suppression. Mechanistically, Abemaciclib consistently lowered the expression of CD44 and TCF7L2 in both parental and sphere cells by inhibiting GSK3β phosphorylation. A pharmacological GSK3β inhibitor produced similar effects, reinforcing the existence of a GSK3β-CD44/TCF7L2 axis. Moreover, orthotopic xenografts confirmed reduced tumor growth and CD44 expression in vivo. Analyses of TCGA and CGGA datasets revealed that the mesenchymal GBM subtype (MES-GBM), linked with poor outcomes, exhibits elevated EMT gene expression. Treatment of MES-like LN229 cells with Abemaciclib resulted in decreased phosphorylation of GSK3β and reductions in EMT-related gene expression. Our findings highlight a novel EMT-suppressive action of Abemaciclib, illustrating its therapeutic potential for targeting the CSCs and for treating the MES-GBM. This research provides mechanistic insights and justification for repurposing Abemaciclib as targeted therapies for aggressive glioblastoma.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1120-1132"},"PeriodicalIF":5.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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