Cell Death & Disease
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2026
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IF 9.6
Yang Shizhou,Ma Yuejiang,Wu Tingting,Huang Xiufeng
Although hypoxia is a well-known key driver of metabolic reprogramming in endometrial cancer (EC), its role in lactate-mediated macrophage activation remains unclear. This study investigates whether hypoxia-mediated lactate metabolism reprogramming facilitated EC progression via macrophages. Our data demonstrated that hypoxia-inducible factor 1 subunit alpha (HIF1A) drives a lactate-regulated metabolic cascade, elevating glycolytic genes and monocarboxylate transporter 3 (MCT3) in EC cells to produce and export more lactate. This lactate is transported to macrophages by MCT1 to drive M2 macrophage polarization. Mechanistically, lactate induces lactylation of Histone 3 in the promoter of DNA methyltransferase 1 (DNMT1) gene and activates transcription in macrophages, leading to the silencing of NHE7 gene expression, a key regulator of intracellular pH. Critically, NHE7 downregulation drives M2 polarization and senescence through the mitogen-activated protein kinase (MAPK) pathway activation in macrophages, ultimately facilitating EC progression. In vivo, we successfully established a xenograft tumor model using Ishikawa cells, and the data further confirmed that NHE7-overexpressing macrophages effectively abrogate exogenous lactate-accelerated xenograft tumor growth, as well as its M2 polarization and senescence. These findings uncover that hypoxia-mediated lactate production and transmission promote tumor-macrophage crosstalk via the DNMT1-NHE7 axis and EC progression, which offers novel therapeutic targets for EC.
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Zhiyu Liu,Yuqi Li,Juan Wang,Yang Zeng,Qilong Wu,Xinyao Zhu,Tao Zhou,Qingfu Deng
Background Prostate cancer (PRAD) is a common malignancy in men, and exposure to soil pollutants may contribute to its development. And exposure to soil pollutant has been linked to its development, as well as to other diseases including cardiovascular disorders, neurological conditions, and additional cancers. Methods This study integrates network toxicology, machine learning, and advanced technologies to investigate the mechanisms through which soil pollutants affect prostate cancer. Network toxicology was used to identify targets and signaling pathways associated with soil pollutants. Target prediction of soil pollutants was performed through SwissTargetPrediction and the Similarity Ensemble Approach (SEA). Prostate cancer-associated target genes were obtained from the Genecards and OMIM databases. Protein-protein interaction analysis further identified key regulatory molecules. Then a predictive model was constructed with 101 machine learning algorithms, identified risk target molecules and assessed the relationship between soil pollutants and prostate cancer risk. Single-cell sequencing examined the expression profiles of these targets in prostate cancer cell types. Molecular docking simulations evaluated the binding affinities between pollutants and target proteins to explore potential molecular mechanisms. Results Ten soil pollutants were analyzed, including dibutyl phthalate (DBP), dioctyl phthalate (DOP), dimethyl phthalate (DMP), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), methyl ethyl ketone (MEK), toluene (TOL), zearalenone (ZEN), ochratoxin A (OTA), and deoxynivalenol (DON). Integration of multiple databases identified 242 potential targets, and protein-protein interaction analysis revealed key regulatory molecules. A prognostic risk model identified 26 risk target molecules. Single-cell sequencing demonstrated their expression profiles in prostate cancer. Kaplan-Meier, univariate, and multivariate Cox regression analyses revealed independent prognostic significance for DNMT1 and MTOR. Molecular docking confirmed that most soil pollutants bind strongly to DNMT1 and MTOR, suggesting disruption of related signaling pathways. Furthermore, experiments were conducted to explore the relationship between soil pollutants and target proteins. Conclusions Various analytical methods to elucidate mechanisms by which soil pollutants contribute to prostate cancer through interactions with key molecular targets DNMT1 and mTOR. These findings inform the prevention and treatment of environmentally related cancers and provide novel insights into the molecular connection between soil pollutants and prostate cancer, and laying the groundwork for preventive and intervention strategies targeting environmentally related cancers.
研究领域:
毒理学
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生物信息学
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环境卫生
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肿瘤学
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计算生物学
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系统生物学
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机器学习
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分子生物学
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高影响因子
Cancer Immunology Research
·
2022
·Vol. 10
·期 4
·525-539
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IF 12.02
Chen Yu,Cai Qiaomei,Pan Chaohu,Liu Wancheng,Li Lili,Liu Junxiao,Gao Meiling,Li Xiaorong,Wang Liguo,Rao Yu,Yang Heng,Cheng Genhong
Inhibitors of cyclin-dependent kinase-2 (CDK2) are commonly used against several solid tumors, and their primary mechanisms of action were thought to include cell proliferation arrest, induction of cancer cell apoptosis and induction of differentiation. Here, we found that CDK2 inhibition by either small molecular inhibitors or genetic Cdk2 deficiency promoted antitumor immunity in murine models of fibrosarcoma and lung carcinoma. Mechanistically, CDK2 inhibition reduced phosphorylation of RB protein and transcription of E2F-mediated DNA methyltransferase 1 (DNMT1), which resulted in increased expression of endogenous retroviral RNA and type I IFN (IFN-I) response. The increased IFN-I response subsequently promoted antitumor immunity by enhancing tumor antigen presentation and CD8 + T-cell infiltration. Our studies provide evidence that inhibition of CDK2 in cancer cells suppresses tumor growth by enhancing antitumor immune responses in the tumor microenvironment, suggesting a new mechanism to enhance antitumor immunity by CDK2 inhibitors.
研究领域:
肿瘤学
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免疫学
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分子生物学
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PubMed
高影响因子
Stem Cells International
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2018
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IF 3.989
Yong-Heng Luo,Juan Chen,En-Hua Xiao,Qiu-Yun Li,Yong-Mei Luo
Demethylating agent zebularine is reported to be capable of inducing differentiation of stem cells by activation of methylated genes, though its function in hepatocyte differentiation is unclear. p38 signal pathway is involved in differentiation of hepatocytes and regulating of DNA methyltransferases 1 (DNMT1) expression. However, little is known about the impact of zebularine on bone marrow mesenchymal stem cells (BMMSCs) and p38 signaling during hepatic differentiation. The present study investigated the effects of zebularine on hepatic differentiation of rabbit BMMSCs, as well as the role of p38 on DNMT1 and hepatic differentiation, with the aim of developing a novel strategy for improving derivation of hepatocytes. BMMSCs were treated with zebularine at concentrations of 10, 20, 50, and 100 μM in the presence of hepatocyte growth factor; changes in the levels of hepatic-specific alpha-fetoprotein and albumin were detected and determined by RT-PCR, WB, and immunofluorescence staining. Expression of DNMT1 and phosphorylated p38 as well as urea production and ICG metabolism was also analyzed. Zebularine at concentrations of 10, 20, and 50 μM could not affect cell viability after 48 h. Zebularine treatment leads to an inhibition of DNMT activity and increase of hepatic-specific proteins alpha-fetoprotein and albumin in BMMSCs in vitro; zebularine addition also induced expression of urea production of and ICG metabolism. p38 signal was activated in BMMSCs simulated with HGF; inhibition of p38 facilitated the synthesis of DNMT1 and albumin in cells. Zebularine restrained DNMT1 and phosphorylated p38 which were induced by HGF. Therefore, this study demonstrated that treatment with zebularine exhibited terminal hepatic differentiation of BMMSCs in vitro in association with hepatocyte growth factor; p38 pathway at least partially participates in zebularine-induced hepatic differentiation of rabbit BMMSCs.
研究领域:
干细胞研究
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分子生物学
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细胞信号传导
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表观遗传学
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高影响因子
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