Heng Gao, Lei Shi, Jinfeng Liu, Yingren Zhao, Fenjing Du, Yingli He, Xin Yang, Ning Song, Juan Wen, Gezhi Zheng
{"title":"foxm1激活的IGF2BP3通过稳定RRM2 mRNA以m6a依赖的方式抑制铁凋亡，从而促进肝癌细胞恶性表型和M2巨噬细胞极化。","authors":"Heng Gao, Lei Shi, Jinfeng Liu, Yingren Zhao, Fenjing Du, Yingli He, Xin Yang, Ning Song, Juan Wen, Gezhi Zheng","doi":"10.1007/s11010-024-05170-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis has a crucial role in human carcinogenesis. N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) suppresses ferroptosis of hepatocellular carcinoma (HCC) cells. Here, we examined the effects and molecular determinants of IGF2BP3-mediated ferroptosis on malignant behaviors of HCC cells.</p><p><strong>Methods: </strong>Ferroptosis was evaluated by measuring the levels of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and lipid ROS. HCC cell malignant phenotypes were evaluated by colony formation assay, wound healing assay, and transwell invasion assay. The CD206<sup>+</sup> M2-like macrophages were assessed by flow cytometry. m6A RNA immunoprecipitation (MeRIP) was applied to assess the m6A modification of ribonucleotide reductase regulatory subunit M2 (RRM2). RNA immunoprecipitation (RIP) assay was performed to evaluate the interaction of IGF2BP3 and RRM2. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were conducted to confirm the interaction between forkhead box M1 (FOXM1) and IGF2BP3.</p><p><strong>Results: </strong>Human HCC tumors showed increased expression of IGF2BP3 compared with adjacent normal tissues. Disruption of IGF2BP3 promoted cell ferroptosis. Moreover, disruption of IGF2BP3 hindered HCC cell growth, invasiveness, and motility and impeded THP1-derived macrophage M2 polarization and migration by inducing ferroptosis. Additionally, IGF2BP3 disruption repressed xenograft growth in vivo. Mechanistically, IGF2BP3 enhanced RRM2 mRNA stability and elevated its protein expression by reading its m6A modification. Overexpression of RRM2 reversed sh-IGF2BP3-mediated ferroptosis and weakened sh-IGF2BP3-mediated suppression of HCC cell malignant phenotypes and macrophage M2 polarization. Furthermore, IGF2BP3 was a downstream target of FOXM1, and knockdown of FOXM1 induced ferroptosis and inhibited cell malignant phenotypes by downregulating IGF2BP3.</p><p><strong>Conclusion: </strong>FOXM1-induced IGF2BP3 upregulation promotes HCC cell malignant behaviors and macrophages M2 polarization by repressing ferroptosis via m6A-dependent regulation of RRM2 mRNA. Targeting FOXM1/IGF2BP3/RRM2 to enhance ferroptosis might be exploited as a potent therapeutic strategy for HCC.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"FOXM1-activated IGF2BP3 promotes cell malignant phenotypes and M2 macrophage polarization in hepatocellular carcinoma by inhibiting ferroptosis via stabilizing RRM2 mRNA in an m6A-dependent manner.\",\"authors\":\"Heng Gao, Lei Shi, Jinfeng Liu, Yingren Zhao, Fenjing Du, Yingli He, Xin Yang, Ning Song, Juan Wen, Gezhi Zheng\",\"doi\":\"10.1007/s11010-024-05170-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Ferroptosis has a crucial role in human carcinogenesis. N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) suppresses ferroptosis of hepatocellular carcinoma (HCC) cells. Here, we examined the effects and molecular determinants of IGF2BP3-mediated ferroptosis on malignant behaviors of HCC cells.</p><p><strong>Methods: </strong>Ferroptosis was evaluated by measuring the levels of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and lipid ROS. HCC cell malignant phenotypes were evaluated by colony formation assay, wound healing assay, and transwell invasion assay. The CD206<sup>+</sup> M2-like macrophages were assessed by flow cytometry. m6A RNA immunoprecipitation (MeRIP) was applied to assess the m6A modification of ribonucleotide reductase regulatory subunit M2 (RRM2). RNA immunoprecipitation (RIP) assay was performed to evaluate the interaction of IGF2BP3 and RRM2. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were conducted to confirm the interaction between forkhead box M1 (FOXM1) and IGF2BP3.</p><p><strong>Results: </strong>Human HCC tumors showed increased expression of IGF2BP3 compared with adjacent normal tissues. Disruption of IGF2BP3 promoted cell ferroptosis. Moreover, disruption of IGF2BP3 hindered HCC cell growth, invasiveness, and motility and impeded THP1-derived macrophage M2 polarization and migration by inducing ferroptosis. Additionally, IGF2BP3 disruption repressed xenograft growth in vivo. Mechanistically, IGF2BP3 enhanced RRM2 mRNA stability and elevated its protein expression by reading its m6A modification. Overexpression of RRM2 reversed sh-IGF2BP3-mediated ferroptosis and weakened sh-IGF2BP3-mediated suppression of HCC cell malignant phenotypes and macrophage M2 polarization. Furthermore, IGF2BP3 was a downstream target of FOXM1, and knockdown of FOXM1 induced ferroptosis and inhibited cell malignant phenotypes by downregulating IGF2BP3.</p><p><strong>Conclusion: </strong>FOXM1-induced IGF2BP3 upregulation promotes HCC cell malignant behaviors and macrophages M2 polarization by repressing ferroptosis via m6A-dependent regulation of RRM2 mRNA. Targeting FOXM1/IGF2BP3/RRM2 to enhance ferroptosis might be exploited as a potent therapeutic strategy for HCC.</p>\",\"PeriodicalId\":18724,\"journal\":{\"name\":\"Molecular and Cellular Biochemistry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-12-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular and Cellular Biochemistry\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1007/s11010-024-05170-2\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular and Cellular Biochemistry","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s11010-024-05170-2","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
FOXM1-activated IGF2BP3 promotes cell malignant phenotypes and M2 macrophage polarization in hepatocellular carcinoma by inhibiting ferroptosis via stabilizing RRM2 mRNA in an m6A-dependent manner.
Background: Ferroptosis has a crucial role in human carcinogenesis. N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) suppresses ferroptosis of hepatocellular carcinoma (HCC) cells. Here, we examined the effects and molecular determinants of IGF2BP3-mediated ferroptosis on malignant behaviors of HCC cells.
Methods: Ferroptosis was evaluated by measuring the levels of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and lipid ROS. HCC cell malignant phenotypes were evaluated by colony formation assay, wound healing assay, and transwell invasion assay. The CD206+ M2-like macrophages were assessed by flow cytometry. m6A RNA immunoprecipitation (MeRIP) was applied to assess the m6A modification of ribonucleotide reductase regulatory subunit M2 (RRM2). RNA immunoprecipitation (RIP) assay was performed to evaluate the interaction of IGF2BP3 and RRM2. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were conducted to confirm the interaction between forkhead box M1 (FOXM1) and IGF2BP3.
Results: Human HCC tumors showed increased expression of IGF2BP3 compared with adjacent normal tissues. Disruption of IGF2BP3 promoted cell ferroptosis. Moreover, disruption of IGF2BP3 hindered HCC cell growth, invasiveness, and motility and impeded THP1-derived macrophage M2 polarization and migration by inducing ferroptosis. Additionally, IGF2BP3 disruption repressed xenograft growth in vivo. Mechanistically, IGF2BP3 enhanced RRM2 mRNA stability and elevated its protein expression by reading its m6A modification. Overexpression of RRM2 reversed sh-IGF2BP3-mediated ferroptosis and weakened sh-IGF2BP3-mediated suppression of HCC cell malignant phenotypes and macrophage M2 polarization. Furthermore, IGF2BP3 was a downstream target of FOXM1, and knockdown of FOXM1 induced ferroptosis and inhibited cell malignant phenotypes by downregulating IGF2BP3.
Conclusion: FOXM1-induced IGF2BP3 upregulation promotes HCC cell malignant behaviors and macrophages M2 polarization by repressing ferroptosis via m6A-dependent regulation of RRM2 mRNA. Targeting FOXM1/IGF2BP3/RRM2 to enhance ferroptosis might be exploited as a potent therapeutic strategy for HCC.
期刊介绍：
Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell.
In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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