LRRFIP1 enhances the Wnt/β-catenin pathway by binding to DVLs in myelodysplastic syndrome

Due to high heterogeneity, diagnosing MDS can be challenging. Consequently, investigating its pathogenesis and progression mechanisms, and seeking novel targets for diagnosis and treatment, are critical issues that require urgent attention. This study aimed to investigate whether LRRFIP1 might contribute to MDS pathogenesis by modulating the Wnt/β-catenin signaling pathway.

In MDS cell lines, mRNA transcriptome sequencing and Dual luciferase reporter gene assays were employed to assess Wnt/β-catenin signaling pathway activity. To explore the biological characteristics of MDS cell lines, CCK8, Annexin-V APC/7-AAD and Annexin V-FITC/PI double staining and fluorescence TUNEL assay, and PI single staining were used.

In MDS cell lines, proliferation was notably higher in LRRFIP1-overexpressing cells compared to silenced ones, while cell apoptosis was lower in the former. mRNA transcriptome sequencing revealed LRRFIP1's involvement in modulating the Wnt/β-catenin signaling pathway. LRRFIP1 was found to positively regulate Wnt/β-catenin pathway activity, and synergy between LRRFIP1 and Dvl was observed in enhancing canonical Wnt signaling. LRRFIP1 overexpression significantly upregulated key genes in Wnt signaling pathway (such as β-catenin, Dvl2, Dvl3 and Wnt) at the mRNA level, and notably upregulated non-phosphorylated β-catenin at the protein level. Moreover, BCL-2 and CyclinD1 protein expression was significantly higher in LRRFIP1-overexpressing cells compared to silenced ones, with even greater expression observed in LRRFIP1/Dvl3 co-overexpressing cells.

LRRFIP1 can promote the proliferation of MDS cells and inhibit apoptosis, and LRRFIP1 and Dvl can synergistically enhance the activity of the Wnt/β-catenin signaling pathway in MDS, thus providing evidence for LRRFIP1's involvement in the pathogenesis of MDS.