Objective · To investigate the effect of V-set domain containing T cell activation inhibitor 1 (VTCN1) on long noncoding RNAs (lncRNAs) and mRNAs in colon cancer cells. Methods · VTCN1 was overexpressedlentivirus plasmid in colon cancer cell line SW1116. RNA was extracted and sequenced. The differentially expressed lncRNAs and mRNAs were compared with the negative control group. The accuracy of RNA sequencing was verifiedreal-time quantitative PCR (qRT-PCR) using three differentially expressed lncRNAs and two mRNAs. BLAST2GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze and predict the functions of these differentially expressed lncRNAs and mRNAs. The online platform GEPIA18 (Gene Expression Profiling Interactive Analysis) was used to analyze the correlation between differentially expressed lncRNAs and survival of patients with colorectal cancer. Results · A total of 167 differential genes, i.e., 39 lncRNAs and 128 mRNAs, were identifiedRNA sequencing in VTCN1 overexpressed SW1116 cells. The results of qRT-PCR were consistent with those of RNA sequencing. Bioinformatics analysis showed that these different genes regulatedVTCN1 may be involved in endoplasmic reticulum protein processing and RNA monitoring signaling pathways. In addition, three lncRNAs (DNA JC9-AS1, HCG27, and RP11-339B21.13), which were significantly up-regulated in colorectal cancer cells overexpressing VTCN1, were also independent predictors of overall survival of colorectal cancer patients. Conclusion · In colon cancer cells, VTCN1 regulates several downstream lncRNAs and mRNAs, which may be involved in endoplasmic reticulum protein processing and mRNA monitoring signaling pathways.