NSD2 Circular RNA Promotes Metastasis Of Colorectal Cancer By Targeting MiR-199b-5p-mediated DDR1 And JAG1 Signalling

Colorectal cancer is one of the common malignant tumors,which seriously affects the quality of life and endangers human life and health.Liver metastasis is the main cause of death in patients with colorectal cancer.Therefore,exploring new molecular mechanisms regulating liver metastasis of colorectal caneer and searching for new tumor markers are particularly urgent for timely monitoring of CRC progression and guiding clinical CRC individualized treatment.Circular RNA(CircRNA)has a complex and diverse generation pattern and plays an important regulatory role in the body.Therefore,it has become a research hotspot in the field of cancer since its discovery.The most studied circRNA is the exonic circular RNA(ecircRNA)enriched in the cytoplasm,which acts as a microRNA(miRNA)sponge to relieve or reduce the inhibitory effect of miRNA on its downstream target genes,Thereby regulating a plurality of tumor-related signaling pathways.In order to study the specific circRNA in the CLM process,we first constructed an animal model of rectal submucosal injection of colorectal cancer liver metastasis,and performed RNA(transcriptome)-sequencing on the rectal tumor tissue and the liver.metastasis tumor tissue.Through the analysis of the sequencing data,we found that the content of circ-NSD2 in liver metastases was significantly higher than that of rectal in situ tumor tissue,so follow-up study was performed with circ-NSD2.Circular RNANSD2(Circ-NSD2)is generated by reverse splicing of exon 1-2 of NSD2 Pre-mRNA,which is 65%distributed in the cytoplasm and 35%in the nucleus.To further investigate the role of circ-NSD2 in CRC metastasis,we found that overexpression of circ-NSD2 enhances the invasion and metastasis of CRC cells by in vivo animal experiments and in vitro cell function experiments,while circ-NSD2 knockdown attenuates CRC Cell invasion and metastasis;In addition,we found that the expression of eirc-NSD2 was significantly higher in the tumor tissues of patients with colorectal cancer than in the corresponding adjacent tissues,and the degree of expression was positively correlated with CRC stage.Through the study of its mechanism,we found that circ-NSD2 functions as a miRNA sponge in CRC cells,and attenuates the downstream target genes DDR1(Discoidin domain receptor tyrosine kinasel)and JAG1(Jagged 1)by adsorbing miR-199b-5p.In conclusion,circ-NSD2 promotes migration,invasion and metastasis of colorectal cancer through the circ-NSD2/miR199b-5p/DDR1/JAG1 axis;and its strong stability and high expression level in CRC could be used as a marker for colorectal tumor detection and provides a new potential target for the diagnosis and further treatment of colorectal cancer.