ObjectiveTo screen and clinically validate prognosis-related differentially expressed long non-coding RNAs (LncRNAs) in colon cancer using gene chip technology.MethodsA cohort of 321 colon cancer patients treated between June 2020 and June 2023 was selected for this study. Among them, 34 patients were used for screening differentially expressed LncRNAs, while 287 patients were used for subsequent validation. Of the 34 patients, 9 who experienced poor prognosis one year post-surgery were categorized into Group A, with the remaining 25 patients were assigned to Group B. Gene chip technology was employed to detect differentially expressed LncRNAs in the tumor tissues of Groups A and B. A competing endogenous RNA (ceRNA) network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Prognosis-related LncRNAs were screened using the LASSO regression model, and the variables identified were included in a multivariate Cox regression model to analyze factors affecting the prognosis of colon cancer.ResultsA total of 227 differentially expressed LncRNAs were screened between Groups A and B, with 162 upregulated and 65 downregulated LncRNAs. The constructed ceRNA network comprised 181 nodes (93 LncRNA nodes, 29 miRNA nodes, and 59 mRNA nodes) and 603 edges. GO enrichment analysis revealed that the differentially expressed LncRNAs were primarily involved in cellular responses to chemical stress, oxidative stress, and external stimuli, including transcriptional regulatory complexes, RNA polymerase Ⅱ transcription regulatory complexes, and the nuclear outer membrane. These LncRNAs were also involved in DNA-binding transcription factor binding, R-SMAD binding, and RNA polymerase Ⅱ-activated transcription factor binding. KEGG enrichment analysis indicated that the differentially expressed LncRNAs were mainly concentrated in the IL-17 signaling pathway, TNF signaling pathway, oxytocin signaling pathway, and NF-κB signaling pathway. LASSO regression identified 11 variables associated with colon cancer prognosis, including LncRNA NEAT1, LncRNA PCAT1, LncRNA CASC11, LncRNA CCAT1, LncRNA PCAT6, LncRNA ZEB1-AS1, LncRNA PSMA3-AS1, LncRNA AC005062.1, LncRNA GAS5, LncRNA MEG3, and LncRNA USP30-AS1. Cox regression analysis revealed that TNM stage, LncRNA CASC11, LncRNA CCAT1, and LncRNA PCAT6 were risk factors for colon cancer prognosis (P<0.05), whereas LncRNA GAS5 and LncRNA MEG3 were protective factors (P<0.05).ConclusionThis study identify 227 differentially expressed LncRNAs in colon cancer patients with varying prognoses. A ceRNA network is successfully constructed, with GO enrichment analysis highlights cellular responses to chemical stress, oxidative stress, and external stimuli, while KEGG enrichment analysis points to significant involvement in the IL-17, TNF, oxytocin, and NF-κB signaling pathways. Clinical validation indicates that LncRNA CASC11, LncRNA CCAT1, and LncRNA PCAT6 are risk factors for colon cancer prognosis, while LncRNA GAS5 and LncRNA MEG3 serve as protective factors.