CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability
Abstract Background Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) is an RNA binding protein with multiple roles in regulation of gene expression at the post-transcriptional level and is implicated in tumorigenesis and progression of numerous cancers including gastric cancer (GC). Ci...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04235-y |
| _version_ | 1797795512452120576 |
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| author | Feifei Yang Qiang Ma Bo Huang Xiaolin Wang Xiaojuan Pan Ting Yu Lingyu Ran Shan Jiang Haiping Li Ye Chen Yuying Liu Ce Liang Junwu Ren Yuying Zhang Shimin Wang Wei Li Bin Xiao |
| author_facet | Feifei Yang Qiang Ma Bo Huang Xiaolin Wang Xiaojuan Pan Ting Yu Lingyu Ran Shan Jiang Haiping Li Ye Chen Yuying Liu Ce Liang Junwu Ren Yuying Zhang Shimin Wang Wei Li Bin Xiao |
| author_sort | Feifei Yang |
| collection | DOAJ |
| description | Abstract Background Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) is an RNA binding protein with multiple roles in regulation of gene expression at the post-transcriptional level and is implicated in tumorigenesis and progression of numerous cancers including gastric cancer (GC). Circular RNAs (circRNAs) are a diverse endogenous noncoding RNA population that have important regulatory roles in cancer. However, circRNAs that regulate the expression of IGF2BP3 in GC is largely unknown. Methods CircRNAs that bound to IGF2BP3 were screened in GC cells using RNA immunoprecipitation and sequencing (RIP-seq). The identification and localization of circular nuclear factor of activated T cells 3 (circNFATC3) were identified using Sanger sequencing, RNase R assays, qRT-PCR, nuclear-cytoplasmic fractionation and RNA-FISH assays. CircNFATC3 expression in human GC tissues and adjacent normal tissues were measured by qRT-PCR and ISH. The biological role of circNFATC3 in GC was confirmed by in vivo and in vitro experiments. Furthermore, RIP, RNA-FISH/IF, IP and rescue experiments were performed to uncover interactions between circNFATC3, IGF2BP3 and cyclin D1 (CCND1). Results We identified a GC-associated circRNA, circNFATC3, that interacted with IGF2BP3. CircNFATC3 was significantly overexpressed in GC tissues and was positively associated with tumor volume. Functionally, the proliferation of GC cells decreased significantly after circNFATC3 knockdown in vivo and in vitro. Mechanistically, circNFATC3 bound to IGF2BP3 in the cytoplasm, which enhanced the stability of IGF2BP3 by preventing ubiquitin E3 ligase TRIM25-mediated ubiquitination, thereby enhancing the regulatory axis of IGF2BP3-CCND1 and promoting CCND1 mRNA stability. Conclusions Our findings demonstrate that circNFATC3 promotes GC proliferation by stabilizing IGF2BP3 protein to enhance CCND1 mRNA stability. Therefore, circNFATC3 is a potential novel target for the treatment of GC. |
| first_indexed | 2024-03-13T03:19:06Z |
| format | Article |
| id | doaj.art-5aa1e929f50845288c399768a9eb7c02 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-13T03:19:06Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-5aa1e929f50845288c399768a9eb7c022023-06-25T11:26:14ZengBMCJournal of Translational Medicine1479-58762023-06-0121111910.1186/s12967-023-04235-yCircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stabilityFeifei Yang0Qiang Ma1Bo Huang2Xiaolin Wang3Xiaojuan Pan4Ting Yu5Lingyu Ran6Shan Jiang7Haiping Li8Ye Chen9Yuying Liu10Ce Liang11Junwu Ren12Yuying Zhang13Shimin Wang14Wei Li15Bin Xiao16College of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityDepartment of Clinical Laboratory, The 89th Hospital of The People’s Liberation ArmyDepartment of Kidney, Southwest Hospital, Army Medical UniversityInstitute for Advanced Study, Shenzhen UniversityCollege of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityCollege of Pharmacy, Chongqing Medical UniversityDepartment of Pharmacy, Chongqing University Cancer HospitalCollege of Pharmacy, Chongqing Medical UniversityAbstract Background Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) is an RNA binding protein with multiple roles in regulation of gene expression at the post-transcriptional level and is implicated in tumorigenesis and progression of numerous cancers including gastric cancer (GC). Circular RNAs (circRNAs) are a diverse endogenous noncoding RNA population that have important regulatory roles in cancer. However, circRNAs that regulate the expression of IGF2BP3 in GC is largely unknown. Methods CircRNAs that bound to IGF2BP3 were screened in GC cells using RNA immunoprecipitation and sequencing (RIP-seq). The identification and localization of circular nuclear factor of activated T cells 3 (circNFATC3) were identified using Sanger sequencing, RNase R assays, qRT-PCR, nuclear-cytoplasmic fractionation and RNA-FISH assays. CircNFATC3 expression in human GC tissues and adjacent normal tissues were measured by qRT-PCR and ISH. The biological role of circNFATC3 in GC was confirmed by in vivo and in vitro experiments. Furthermore, RIP, RNA-FISH/IF, IP and rescue experiments were performed to uncover interactions between circNFATC3, IGF2BP3 and cyclin D1 (CCND1). Results We identified a GC-associated circRNA, circNFATC3, that interacted with IGF2BP3. CircNFATC3 was significantly overexpressed in GC tissues and was positively associated with tumor volume. Functionally, the proliferation of GC cells decreased significantly after circNFATC3 knockdown in vivo and in vitro. Mechanistically, circNFATC3 bound to IGF2BP3 in the cytoplasm, which enhanced the stability of IGF2BP3 by preventing ubiquitin E3 ligase TRIM25-mediated ubiquitination, thereby enhancing the regulatory axis of IGF2BP3-CCND1 and promoting CCND1 mRNA stability. Conclusions Our findings demonstrate that circNFATC3 promotes GC proliferation by stabilizing IGF2BP3 protein to enhance CCND1 mRNA stability. Therefore, circNFATC3 is a potential novel target for the treatment of GC.https://doi.org/10.1186/s12967-023-04235-ycircNFATC3IGF2BP3TRIM25CCND1Gastric cancer |
| spellingShingle | Feifei Yang Qiang Ma Bo Huang Xiaolin Wang Xiaojuan Pan Ting Yu Lingyu Ran Shan Jiang Haiping Li Ye Chen Yuying Liu Ce Liang Junwu Ren Yuying Zhang Shimin Wang Wei Li Bin Xiao CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability Journal of Translational Medicine circNFATC3 IGF2BP3 TRIM25 CCND1 Gastric cancer |
| title | CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability |
| title_full | CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability |
| title_fullStr | CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability |
| title_full_unstemmed | CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability |
| title_short | CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability |
| title_sort | circnfatc3 promotes the proliferation of gastric cancer through binding to igf2bp3 and restricting its ubiquitination to enhance ccnd1 mrna stability |
| topic | circNFATC3 IGF2BP3 TRIM25 CCND1 Gastric cancer |
| url | https://doi.org/10.1186/s12967-023-04235-y |
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