ZNRF3 contributes to the growth of lung carcinoma via inhibiting Wnt/β-catenin pathway and is regulated by miR-93

Jichan Shi, Xiangao Jiang, Zhijie Yu, Guiqing He, Hongye Ning, Zhengxing Wu, Yuwei Cai, Hehe Yu, Aiqiong Chen

Lung carcinoma is the most common cancer with increasing morbidity, inefficient therapeutic modality, and poor prognosis, due to the lack of understanding of its related molecular mechanism. ZNRF3 is a newly identified negative regulator of Wnt signaling. In this study, we found that ZNRF3 level is reduced in lung carcinoma compared with normal lung tissue and its expression level is positively correlated with the survival of lung cancer patients. Restoration of ZNRF3 suppressed the proliferation and cell cycle progression of lung cancer cell lines. Suppression of ZNRF3 expression in normal lung cells increased the proliferation rates. In an animal model, ZNRF3 was shown to suppress the growth of lung cancer xenografts. ZNRF3 was shown to negatively regulate the activation of Wnt signaling in lung cancerous and normal cells. Further studies revealed that ZNRF3 is a target of miR-93, an oncogenic microRNA (miRNA) for lung cancer progression. Collectively, we found that miR-93/ZNRF3/Wnt/β-catenin regulatory network contributes to the growth of lung carcinoma. Targeting this pathway may be a promising strategy for lung cancer therapy.