Background: Our previous study shows that LINC01278 inhibits the malignant proliferation and invasion of papillary thyroid carcinoma (PTC) cells by regulating the miR-376c-3p/DNM3 axis. However, the regulation mechanism of LINC01278 expression in PTC cells is still unclear. Methods: The luciferase reporter and ChIP assays were used to confirm the binding of LEF-1 to the putative promoter site of LINC01278 gene. The RNA immunoprecipitation and RNA pulldown were used to determine the enrichment of LINC01278 in beta-catenin protein. The proteasome inhibitors (MG132) was used for detecting the beta-catenin ubiquitination-proteasome degradation. Wnt/beta-catenin specific agonists (LiCI), inhibitors (WiKI4) and TOP/FOP-flash reporter assay were used for detecting the activation of Wnt/beta-catenin signal. Western blot was used to detected the expression of target proteins. Results: The online PROMO algorithm determines a putative LEF-1 binding site on LINC01278 promoter, the LEF-1 binds to the putative promoter site of LINC01278 gene, and beta-catenin enhances the binding of LEF-1 to the LINC01278 gene promoter. Furthermore, LINC01278 negatively regulated the protein accumulation of beta-catenin in the cytoplasm, into nucleus, and ultimately inhibited the transcription of downstream target genes activated by Wnt/beta-catenin signal. The results of RNA immunoprecipitation and RNA pulldown proved the direct binding of LINC01278 to beta-catenin protein. In addition, the combination of LINC01278 and beta-catenin promotes the beta-catenin ubiquitination-proteasome degradation. Conclusion: In summary, we found the transcriptional activation of LINC01278 by the beta-catenin/LEF-1 transcription factor, and the negative feedback regulation of LINC01278 on beta-catenin signal.