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Characterization of circSCL38A1 as a novel oncogene in bladder cancer via targeting ILF3/TGF-β2 signaling axis
Peilong Li1,2, Qi Mi1, Suzhen Yan1,2
1Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong, 250033, China.
Abstract:
The regulatory role of circRNAs in cancer metastasis has become a focused issue in recent years. To date, however, the discovery of novel functional circRNAs and their regulatory mechanisms via binding with RBPs in bladder cancer (BC) are still lacking. Here, we screened out circSLC38A1 based on our sequencing data and followed validation with clinical tissue samples and cell lines. Functional assays showed that circSLC38A1 promoted BC cell invasion in vitro and lung metastasis of mice in vivo. By conducting RNA pull-down, mass spectrum, and RIP assays, circSLC38A1 was found to interact with Interleukin enhancer-binding factor 3 (ILF3), and stabilize ILF3 protein via modulating the ubiquitination process. By integrating our CUT&Tag-seq and RNA-seq data, TGF-β2 was identified as the functional target of the circSLC38A1-ILF3 complex. In addition, m6A methylation was enriched in circSLC38A1 and contributed to its upregulation. Clinically, circSLC38A1 was identified in serum exosomes of BC patients and could distinguish BC patients from healthy individuals with a diagnostic accuracy of 0.878. Thus, our study revealed an essential role and clinical significance of circSLC38A1 in BC via activating the transcription of TGF-β2 in an ILF3-dependent manner, extending the understanding of the importance of circRNA-mediated transcriptional regulation in BC metastasis.
Insights
This study identifies circSLC38A1 as a key regulator in bladder cancer (BC) metastasis. It promotes BC cell invasion and lung metastasis by stabilizing ILF3 and activating TGF-β2 transcription, showing potential as a diagnostic biomarker.
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- Circular RNAs (circRNAs) are increasingly recognized for their regulatory roles in cancer metastasis.
- Mechanisms of circRNA-RBP interactions in bladder cancer (BC) metastasis remain underexplored.
- Novel functional circRNAs and their regulatory pathways in BC require identification.
Purpose of the Study:
- To identify and characterize novel functional circRNAs involved in bladder cancer metastasis.
- To elucidate the regulatory mechanism of circSLC38A1, including its interaction with RNA-binding proteins (RBPs).
- To assess the clinical significance of circSLC38A1 as a diagnostic biomarker for bladder cancer.
Main Methods:
- Screening and validation of circRNAs using sequencing data and clinical tissue samples.
- In vitro and in vivo functional assays to assess cell invasion and metastasis.
- RNA pull-down, mass spectrometry, and RIP assays to identify protein interactions.
- CUT&Tag-seq and RNA-seq to identify target genes.
- Analysis of m6A methylation and exosomal circRNA detection in patient serum.
Main Results:
- circSLC38A1 was identified and validated as a promoter of BC cell invasion and lung metastasis.
- circSLC38A1 interacts with Interleukin enhancer-binding factor 3 (ILF3), stabilizing it by modulating ubiquitination.
- The circSLC38A1-ILF3 complex activates TGF-β2 transcription; m6A methylation contributes to circSLC38A1 upregulation.
- circSLC38A1 in serum exosomes accurately distinguishes BC patients from healthy individuals (diagnostic accuracy 0.878).
Conclusions:
- circSLC38A1 plays a critical role in bladder cancer metastasis through ILF3-dependent activation of TGF-β2 transcription.
- circSLC38A1 represents a potential diagnostic biomarker for bladder cancer.
- This study enhances the understanding of circRNA-mediated transcriptional regulation in cancer metastasis.
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