Molecular Carcinogenesis最新文献

{"title":"Therapeutic Potential of IL-37 in Cervical Cancer: Suppression of Tumour Progression and Enhancement of CD47-Mediated Macrophage Phagocytosis.","authors":"Yuan Feng, Lianlian Feng, Bingyu Wang, Teng Zhang, Baoxia Cui","doi":"10.1002/mc.23855","DOIUrl":"10.1002/mc.23855","url":null,"abstract":"<p><p>As a promising therapeutic approach, immunotherapy is being extensively investigated in cervical cancer. Although immunotherapy has been validated to improve progression-free survival and overall survival in clinical trials, the overall response rate for cervical cancer remains inadequate, necessitating further improvement. Interleukin (IL)-37, an emerging immunomodulator, exhibits antitumour potentials by inhibiting tumour progression and regulating tumour-associated macrophage recognition. We found a significant downregulation of IL-37 expression in cervical cancer, correlated with a poor prognosis. Moreover, the upregulation of IL-37 expression exhibited a suppressive effect on various tumorigenic processes, suppressing the proliferation, invasion, migration, apoptosis and angiogenesis of tumour cells. We also found that the upregulation of IL-37 suppressed cluster of differentiation 47 (CD47) expression in tumour cells via suppression of the signal transducer and activator of transcription 3 (STAT3) expression and phosphorylation, thereby enhancing macrophage recognition and phagocytosis to tumour cells, ultimately reducing immune evasion. Overall, our study highlighted the crucial role of IL-37 in antitumour efficacy and downregulating the expression of CD47 in tumour cells to reduce immune evasion, suggesting the potential of IL-37 as a prognostic biomarker in cervical cancer and offering innovative therapeutic strategies to improve cancer treatment outcomes.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"425-439"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770380","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":"RNA Methyltransferase NSUN5 Promotes Esophageal Cancer via 5-Methylcytosine Modification of METTL1.","authors":"Yuanbo Cui, Zhaoyang Hu, Chunyan Zhang","doi":"10.1002/mc.23857","DOIUrl":"10.1002/mc.23857","url":null,"abstract":"<p><p>Aberrant RNA modifications can drive carcinogenic transformation and tumor progression, with 5-methylcytosine (m5C) emerging as one of the predominant RNA modifications in eukaryotic cells. However, the function and molecular mechanisms of m5C in esophageal cancer (ESCA) remain insufficiently defined. Here we report that the m5C methyltransferase NOP2/Sun domain family member 5 (NSUN5) is significantly upregulated in ESCA tumors and shows promising diagnostic potential. Functionally, knockdown of NSUN5 impairs the proliferation capacity of ESCA cells and arrests cell cycle at the G0/G1 phase, while enforced expression of NSUN5 accelerates ESCA progression. In vivo, deficiency of NSUN5 significantly reduces tumor growth in a cell-based xenograft mouse model. Mechanistically, NSUN5 correlates with the oncogenic methyltransferase like 1 (METTL1), positively regulating its expression; NSUN5 binds directly to the METTL1 transcript, facilitating its m5C modification in ESCA cells. Additionally, overexpression of METTL1 effectively counteracts the tumor-suppressive effects resulting from NSUN5 ablation in both in vitro and in vivo settings. A comprehensive pan-cancer analysis further underscores NSUN5's essential role in digestive system tumors, with downregulation of NSUN5 notably inhibiting gastric and colon cancer cell growth. These findings provide new insights into epigenetic regulation in ESCA and propose the NSUN5/METTL1 axis as a promising therapeutic target for this malignancy.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"399-409"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Suppression of miR-137 Induces RNF4 Expression, Facilitating Wnt Signaling in Colorectal Cancer.","authors":"Yazhou Wu, Hanhua Li, Yin Long, Zhenzhen Zhang, Fanping Zhang, Runyu Pan, Leijun Meng, Zhan Ma, Kaijing Wang, Bing Zheng, Zhonghong Qie, Wei Gao","doi":"10.1002/mc.23859","DOIUrl":"10.1002/mc.23859","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a significant health issue worldwide. Recent studies highlight the critical role of miRNAs in CRC development, particularly miR-137, which acts as a key tumor suppressor. Despite its known role, further exploration of miR-137's downstream signaling is needed to understand its biology and therapeutic potential. We examined the methylation status of miR-137 using one TCGA data and three GEO data sets. A clinical validation cohort of 78 samples was analyzed using MSP for miR-137 promoter methylation. Various in vitro molecular/cellular and animal experiments were conducted to elucidate miR-137's role in CRC. Bioinformatic analysis indicated frequent methylation of miR-137 in CRC tissues, correlating with suppressed expression. EZH2-mediated H3K27 trimethylation silences miR-137 in CRC cells by increasing chromatin compaction, reversible by EZH2 siRNA or inhibitor GSK343. miR-137 inhibits CRC cell proliferation, migration, invasion, and xenograft tumor growth, confirming its tumor-suppressive role. Using the miRWalk repository showed that miR-137 regulates the Wnt signaling pathway by reducing typical protein expression in HCT116 and SW480 cells. miR-137 directly targets RNF4, leading to its downregulation at transcriptional and protein levels, with an observed inverse correlation in CRC tissues. miR-137 accelerates c-Myc and β-catenin degradation by inhibiting RNF4, impacting protein stability and Wnt pathway inhibition. miR-137 is epigenetically silenced through DNA methylation and EZH2-mediated H3K27 trimethylation. It regulates the Wnt signaling pathway by targeting RNF4, leading to c-Myc and β-catenin destabilization. Restoring miR-137 or inhibiting RNF4 suppresses CRC cell proliferation, migration, invasion, and tumor growth, highlighting its therapeutic potential in CRC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"475-489"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Downregulation of SLC7A11 by Bis(4-Hydroxy-3,5-Dimethylphenyl) Sulfone Induces Ferroptosis in Hepatocellular Carcinoma Cell.","authors":"Liyi Zou, Taomin Zhang, Cui Yang, Weijing Liu, Aamir Fahira, Dongli Yang, Biao Zheng, Xiaojun Yao, Yi Liu, Zunnan Huang","doi":"10.1002/mc.23874","DOIUrl":"https://doi.org/10.1002/mc.23874","url":null,"abstract":"<p><p>The progression of tumors has been demonstrated to have a strong correlation with ferroptosis. Bis(4-hydroxy-3,5-dimethylphenyl) sulfone (TMBPS) has been shown to effectively inhibit the proliferation of hepatocellular carcinoma (HCC), but its underlying mechanism is not clear. In this study, ferrostatin-1 (Fer-1) was employed to explore whether the death of HCC cells caused by TMBPS is related to ferroptosis. The intracellular lipid peroxides, Fe²⁺, malondialdehyde (MDA), GSH/GSSG, mitochondrial morphology, and potential of HCC cells were detected after TMBPS treatment. The target of TMBPS was predicted by the molecular docking approach and verified via quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and cellular heat transfer assay (CETSA). Our results revealed that Fer-1 effectively reversed the cell death induced by TMBPS in HCC cells. Treatment with TMBPS induced typical ferroptosis features, including increased levels of intracellular lipid peroxides, Fe²⁺, and MDA, along with a decreased GSSH/GSH ratio and mitochondrial potential. These effects were reversed by overexpressing SLC7A11. These findings suggest that the cell death triggered by TMBPS in HCC cells is linked to ferroptosis, potentially mediated through the inhibition of SLC7A11 expression.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":"64 3","pages":"580-596"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma Metabolomic Signatures of H. pylori Infection, Alcohol Drinking, Smoking, and Risk of Gastric Cancer.","authors":"Yuhui Yu, Zhonghua Zheng, Xinxiang Gao, Yuanliang Gu, Min Zhang, Beiping Hu, Qian Gao, Zhe Li, Yan Chen, Qian Li, Fang Shen, Meng Zhu, Dong Hang, Qiang Zhan, Lu Wang, Chong Shen, Xiangfeng Lu, Dongfeng Gu, Hongxia Ma, Hongbing Shen, Guangfu Jin, Caiwang Yan","doi":"10.1002/mc.23851","DOIUrl":"10.1002/mc.23851","url":null,"abstract":"<p><p>Circulating metabolic profiles have shown promising potential in identifying high-risk populations for various diseases, while metabolic perturbation plays an important role in gastric cancer. In this study, we conducted a cross-sectional study with 1800 participants to identify plasma metabolite signatures associated with environmental risk factors of gastric cancer. Subsequently, we evaluated the association between these signatures and gastric cancer risk in a nested case-control study involving 326 gastric cancer cases and 326 matched cancer-free controls. We conducted mediation analyses to elucidate the potential impact of metabolites on the association between environmental factors and gastric cancer. In the cross-sectional study, we identified 46 metabolites associated with Helicobacter pylori (H. pylori) infection, 365 with alcohol drinking, and 154 with smoking status. In the nested case-control study, 60 plasma metabolites, comprising 30 lipids, 15 amino acids, 6 xenobiotics, 3 nucleotides, 2 cofactors and vitamins, 2 carbohydrate, 1 energy, and 1 peptide, were associated with gastric cancer risk. A one-standard deviation increment in the H. pylori infection-related metabolomic signature was associated with an increased risk of gastric cancer (OR = 1.66, 95% CI: 1.32-2.09, p = 1.62 × 10^-5). Furthermore, the effect of H. pylori infection on gastric cancer was partially mediated by the metabolomic signature (23.28%, 95% CI: 0.09-0.56) or adenine (13.69%, 95% CI: 0.05-0.31). In conclusion, we have identified metabolites associated with environmental factors and demonstrated the association between the H. pylori infection signature and gastric cancer risk. The findings provide novel insights into characterizing high-risk population for gastric cancer.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"463-474"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Levels of Bile Acid Metabolism Are Associated With Alterations of Gut Microbes in Hepatocellular Carcinoma.","authors":"Zhihao Yang, Fengqin Zhou, Daqin Zhan, Pengcheng Li, Jun Pan","doi":"10.1002/mc.23869","DOIUrl":"10.1002/mc.23869","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is viewed as a metabolism associated disease, and bile acid metabolism is reported to occupy a significant role in the progression of HCC. However, little is known about the association between gut microbes and bile acid metabolism in HCC. Our study was designed to clarify the role of bile acid metabolism and microbiome in the progression of HCC. We investigated the relationship between bile acid metabolism and prognosis and immune cells by mining GSE14520. We studied the microbial profiles and metabolic alterations between the low bile acid group and high bile acid group using 16S rRNA sequencing and metabolomics. HCC patients in the high bile acid metabolism group showed better survival outcome compared with those in the low bile acid metabolism. Immune analysis displayed the close correlation between low bile acid metabolism and infiltration of CD4 + T cells, and the close relationship between high bile acid metabolism and infiltration of CD8 + T cells, macrophage cells in HCC. 16S rRNA sequencing results demonstrated that Blautia, Ruminococcus_gnavus_group, Erysipelotrichaceae_UCG-003 were mostly enriched in the low bile acid group. Metabolomics of the 109 fecal samples showed that the most enriched metabolites in the low total bile acid group were dihydrocytochalasin B, cucurbic acid and 27-Norcholestanehexol. Finally, KEGG enrichment analysis identified secondary bile acid biosynthesis and endocrine resistance as the most significant metabolic pathways. High bile acid metabolism was associated with more infiltration of CD8 + T cells, macrophage cells, and better prognosis in HCC. Levels of bile acid were significantly associated with altered gut microbes and metabolites in HCC. Further research related to gut microbes and bile acid metabolism may provide a novel insight into the pathogenesis and therapeutic strategy of HCC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"543-551"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGB3 Contributes to Anti-PD-1 Resistance by Inhibiting IFN-γ-Driven Ferroptosis in TNBC.","authors":"Bo Luo, Hongmei Zheng, Gai Liang, Yan Luo, Qu Zhang, Xiang Li","doi":"10.1002/mc.23861","DOIUrl":"10.1002/mc.23861","url":null,"abstract":"<p><p>Our previous studies showed HMGB3 expression may correlate with immunotherapy efficacy in breast cancer patients. Here, we investigated whether HMGB3 overexpression has an impact on anti-PD-1 therapy in triple-negative breast cancer (TNBC) and its molecular mechanisms. Animal models were established to observe the effect of HMGB3 on sensitivity to anti-PD-1 treatment. Correlation of HMGB3 expression and ferroptosis preventive proteins in TNBC patients' tissues with anti-PD-1 therapy efficacy was analyzed. The impact of HMGB3 on IFN-γ (Interferon-gamma) inhibitory effects and signaling was examined in human TNBC cells where HMGB3 expression was knocked down using siRNA. Moreover, TNBC cells stably transfected with lentiviral vectors containing cDNA of HMGB3 were also used to confirm the effect of overexpression of HMGB3 on IFN-γ inhibitory effect and signaling. Effect of HMGB3 on IFN-γ-driven ferroptosis and ferroptosis-associated protein expression were also investigated. Correlation of HMGB3 and IRF1 and GPX4 expression in patient's cancer tissue were also investigated. Our results demonstrated that HMGB3 expression contributes to resistance to anti-PD-1 therapy in vivo. HMGB3 expression correlated with treatment efficacy of immunotherapy and survival in TNBC patients. HMGB3 silence decreased resistance of breast cancer cells to IFN-γ cytotoxic effect, while HMGB3 overexpression increased resistance of these cancer cells. HMGB3 silence increased STAT1 phosphorylation and IRF1 expression upon IFN-γ treatment compared with control. Overexpression of HMGB3 inhibited STAT1 phosphorylation and IFN-γ signaling in TNBC cells. Moreover, HMGB3 also increased STAT3 activation and had an effect of interaction between STAT1 and STAT3. HMGB3 overexpression decreased IFN-γ-driven ferroptosis in TNBC cells. HMGB3 increased ferroptosis-inhibitory proteins (SLC7A11, GPX4, and SLC3A2) expression in TNBC cells. Ferroptosis inhibition recovers resistance to anti-PD-1 therapy in vivo. Immunohistochemistry showed HMGB3 expression correlated with ferroptosis-associated proteins and IRF1 expression in breast cancer tissue. HMGB3 contributes to anti-PD-1 resistance by inhibiting IFN-γ-driven ferroptosis in TNBC which suggested HMGB3 is a potential co-target with anti-PD-1 therapy for TNBC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"490-501"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MFSD2A Overexpression Inhibits Hepatocellular Carcinoma Through TGF-β/Smad Signaling.","authors":"Chaowen Xiao, Xinyang Zhao, Zouxiao Hu, Guanbao Long","doi":"10.1002/mc.23875","DOIUrl":"https://doi.org/10.1002/mc.23875","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver and has a high mortality. Major facilitator superfamily domain containing 2 (MFSD2A) was previously demonstrated to inhibit tumor progression in several cancers. Here, we elucidated the association between MFSD2A expression and HCC progression and also investigated the underlying mechanism. The online tools were utilized to evaluate MFSD2A expression in HCC samples and predict the prognostic significance of MFSD2A in HCC patients. The biological role of MFSD2A in HCC cellular processes was examined by colony formation, wound healing, transwell, and western blotting. The in vivo role of MFSD2A in HCC was investigated in a xenograft tumor model. The miRNAs and RNA-binding proteins potentially targeting MFSD2A were identified using bioinformatics prediction tools. Luciferase reporter, RNA immunoprecipitation, actinomycin D, and immunofluorescence assays were performed to investigate the molecule mechanisms of MFSD2A. Transforming growth factor (TGF)-β1/Small mothers against decapentaplegic (Smad) signaling was detected using western blot analysis. We found that MFSD2A expression was significantly downregulated in HCC patients and cells and its downregulation predicted a poor prognosis. MFSD2A overexpression repressed HCC cell proliferation, migration, invasion, the epithelial-to-mesenchymal transition in vitro, as well as inhibited HCC tumor growth in vivo. MFSD2A was targeted by miR-3189-3p. High-density lipoprotein binding protein (HDLBP) inhibited MFSD2A expression by binding to and destabilizing MFSD2A mRNA. MFSD2A significantly suppressed activation of TGF-β/Smad signaling in HCC cells. Knockdown of MFSD2A abrogated the inhibitory effect of miR-3189-3p inhibitor on HCC cellular processes, and overexpression of MFSD2A reversed the tumor-promoting effect of HDLBP overexpression. Overall, MFSD2A exerts a tumor-inhibiting effect in HCC via suppression of TGF-β/Smad signaling, suggesting that MFSD2A may be a promising target for HCC therapy.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":"64 3","pages":"597-611"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Bioinformatics Analysis and Experimental Study of NLRP12 Reveal Its Prognostic Value and Potential Functions in Ovarian Cancer.","authors":"Zhihui Xie, Tiantian Yang, Chuchu Zhou, Zixin Xue, Jianjun Wang, Feng Lu","doi":"10.1002/mc.23854","DOIUrl":"10.1002/mc.23854","url":null,"abstract":"<p><p>NLRP12 plays a significant role in cellular functional behavior and immune homeostasis, influencing inflammation, tumorigenesis, and prognosis. This study aimed to explore its specific effects on the tumor microenvironment (TME) and its contribution to heterogeneity in ovarian cancer (OV) through bioinformatics analysis and experimental verification. Utilizing various bioinformatics databases and clinical specimens, we investigated NLRP12 expression and its relationship with OV prognosis and immune infiltration. In vitro assays were conducted to assess the impact of NLRP12 on the proliferation and invasion of OV cells. Our findings indicate that NLRP12 is upregulated in OV, with high expression correlating with a negative prognosis. Furthermore, NLRP12 expression demonstrated a positive correlation with the infiltration of various immune cells and the expression of immune checkpoint molecules in OV. Analysis of The Cancer Immunome Atlas (TCIA) database revealed that OV patients with lower NLRP12 expression may exhibit an enhanced response to immunotherapy, particularly CTLA4 blockers, a finding validated in animal experiments. Additionally, the study emphasized the role of NLRP12 in influencing the prognosis of OV patients by promoting epithelial-mesenchymal transition (EMT) in ovarian cancer cells. Finally, we identified a potential therapeutic compound, Schisandrin B (Schi B), which decreases NLRP12 expression in ovarian cancer cells by binding to the transcription factor SPI1 associated with NLRP12. Our findings suggest that NLRP12 serves as a crucial immune-related biomarker predicting poor outcomes in OV, and targeting NLRP12 may represent a promising therapeutic approach for OV patients in the future.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"383-398"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXN3 Downregulation in Colorectal Cancer Enhances Tumor Cell Stemness by Promoting EP300-Mediated Epigenetic Upregulation of SOX12.","authors":"Yanjie Xu, Ke Xie, Ling Li, Zhong Li, Qicheng Lu, Jin Feng","doi":"10.1002/mc.23852","DOIUrl":"10.1002/mc.23852","url":null,"abstract":"<p><p>Cancer stemness plays a crucial role in promoting the progression of colorectal cancer (CRC). Forkhead box N3 (FOXN3) is a tumor suppressor protein. Herein, we investigated the role of FOXN3 in the regulation of CRC cell stemness. Cell viability, proliferation, migration, and invasion were assessed utilizing cell counting kit-8 assay, 5-ethynyl-20-deoxyuridine assay, and Transwell assay, respectively. Cell-sphere formation was assessed using a sphere-forming assay. The enrichment of H3K27ac modifications at the SRY-related HMG-box 12 (SOX12) promoter, interactions among FOXN3, SOX12, and E1A binding protein p300 (EP300) were analyzed using chromatin immunoprecipitation or dual luciferase reporter assays. We found that FOXN3 overexpression inhibited CRC cell proliferation, migration, invasion, stemness, and tumor formation in mice by inactivating the Wnt/β-catenin signaling, while these effects of FOXN3 overexpression were reversed by the overexpression of SOX12. Mechanistically, EP300 increased SOX12 expression in CRC cells by promoting H3K27ac enrichment in the SOX12 promoter. In addition, FOXN3 transcriptionally inhibited EP300 expression in CRC cells by binding to the EP300 promoter. As expected, EP300 overexpression weakened the inhibitory effect of FOXN3 overexpression on CRC cell stemness. Collectively, FOXN3 upregulation inhibited CRC cell stemness by suppressing EP300-mediated epigenetic upregulation of SOX12.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"410-424"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}