2. Academic Validation
  3. CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability

CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability

  • J Transl Med. 2023 Jun 20;21(1):402. doi: 10.1186/s12967-023-04235-y.
Feifei Yang # 1,  Qiang Ma # 1 2,  Bo Huang 1,  Xiaolin Wang 1,  Xiaojuan Pan 1,  Ting Yu 3,  Lingyu Ran 4,  Shan Jiang 5,  Haiping Li 1,  Ye Chen 1,  Yuying Liu 1,  Ce Liang 1,  Junwu Ren 1,  Yuying Zhang 1,  Shimin Wang 1,  Wei Li 6,  Bin Xiao 7
Affiliations

Affiliations

  • 1 College of Pharmacy, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 2 Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People's Republic of China.
  • 3 Department of Clinical Laboratory, The 89th Hospital of The People's Liberation Army, Weifang, 261000, People's Republic of China.
  • 4 Department of Kidney, Southwest Hospital, Army Medical University, Chongqing, 400038, People's Republic of China.
  • 5 Institute for Advanced Study, Shenzhen University, Shenzhen, 518055, People's Republic of China.
  • 6 Department of Pharmacy, Chongqing University Cancer Hospital, Chongqing, 400030, People's Republic of China. liwei.tmmu@163.com.
  • 7 College of Pharmacy, Chongqing Medical University, Chongqing, 400016, People's Republic of China. binxiaocqmu@cqmu.edu.cn.
  • # Contributed equally.
PMID: 37340423 DOI: 10.1186/s12967-023-04235-y
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.

Keywords

CCND1; Gastric cancer; IGF2BP3; TRIM25; circNFATC3.

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