IFIT3-DVL interaction promotes malignant progression of lung squamous cell carcinoma and large-cell lung carcinoma via canonical WNT signaling.

Interferon-induced protein with tetratricopeptide repeat 3 (IFIT3) is involved in malignant progression. However, little information is available regarding its expression and detailed mechanisms in lung cancer. Herein, the clinicopathological significance of IFIT3 expression in lung squamous cell carcinoma (LUSC) and large-cell lung carcinoma (LCLC) specimens was assessed. IFIT3-overexpression and IFIT3-knockout LUSC/LCLC cells were generated both in vitro and in vivo. IFIT3 overexpression is correlated with advanced tumor-node-metastasis stage, lymph node metastasis, and poor prognosis in patients with LUSC and LCLC. IFIT3 promotes the malignant phenotypes of LUSC/LCLC cells in vitro and in vivo. The interaction between IFIT3 and dishevelled (DVL) in the cytoplasm of LUSC/LCLC cells was identified. Among DVL isoforms (DVL1, DVL2, DVL3), IFIT3-DVL2 interaction most prominently activates canonical wingless-type MMTV integration site family (WNT) signaling. This interaction promotes the phosphorylation of DVL2 at threonine 224 to increase the phosphorylation levels of glycogen synthase kinase-3β at serine nine and β-catenin at serine 675 and the expression of active β-catenin. Consequently, β-catenin nuclear translocation is elevated to activate β-catenin/TCF mediated transcription and upregulate the expressions of target genes of canonical WNT pathway (Cyclin D1, c-MYC, AXIN2) and the protein factors related to cell malignancy (CDK4/6, CDC42, MMP2/7/9). DVL2 knockdown or XAV-939 significantly abrogates above effects mediated by IFIT3 (p < 0.05). Overall, we demonstrated a novel signal transduction pathway where IFIT3 interacts with DVL2 to stabilize cytosolic β-catenin and promote β-catenin nuclear translocation via DVL2 phosphorylation, enhancing canonical WNT signaling activity and providing a potential target for clinical intervention in LUSC and LCLC.