In the present study, we found that TRIM21 positively regulated CRC cell proliferation and DNA replication through TCF3/MCM2/5 axis, and the regulation of TCF3 by TRIM21 was E3 ligase-independent, as we performed Co-IP experiment but found no interaction between TRIM21 and TCF3 proteins. This evidence concerns the gene TRIM21 and colorectal carcinoma.