Lung cancer has been notorious for its lack of advance in clinical therapy, urging for effective therapeutic targets. WD repeat-containing protein 74 (WDR74) has previously been implicated in tumorigenesis, but its mechanistic functions remain not well understood. Herein, WDR74 expression was observed to be increased upon lung cancer progression from healthy normal tissues to the primary cancer and further to the metastatic cancer. Through gain- and loss-of-function approaches, we found that WDR74 regulated lung cancer cell proliferation, cell cycle progression, chemoresistance and cell aggressiveness in vitro. Moreover, a xenograft mouse model disclosed that WDR74 knockout inhibited lung cancer growth and metastasis, whereas WDR74 overexpression reciprocally enhanced these characteristics. Mechanistically, WDR74 promoted nuclear β-catenin accumulation and drove downstream Wnt-responsive genes, thus revealing that WDR74 activated the Wnt/β-catenin signaling pathway. Collectively, WDR74 inducing nuclear β-catenin accumulation and driving the downstream Wnt-responsive genes expression facilitates lung cancer growth and metastasis. WDR74 can serve as a candidate target for the prevention and treatment of lung cancer in clinic.

中文翻译：

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WDR74诱导核β-连环蛋白积累并激活Wnt反应基因，从而促进肺癌的生长和转移。

肺癌因缺乏临床治疗方面的进展而臭名昭著，敦促寻找有效的治疗靶标。包含WD重复序列的蛋白74（WDR74）以前已被牵涉到肿瘤发生，但其机理功能仍不为人所知。在本文中，观察到WDR74表达在肺癌从健康正常组织发展为原发癌并进一步发展为转移性癌症时增加。通过功能获得和丧失功能的方法，我们发现WDR74在体外调节肺癌细胞的增殖，细胞周期进程，化学抗性和细胞侵袭性。此外，异种移植小鼠模型显示，WDR74基因敲除抑制了肺癌的生长和转移，而WDR74的过表达则相应地增强了这些特征。机械上，WDR74促进核β-连环蛋白的积累并驱动下游Wnt反应基因，从而揭示WDR74激活了Wnt /β-catenin信号通路。集体地，WDR74诱导核β-连环蛋白积累并驱动下游Wnt反应基因表达促进肺癌的生长和转移。WDR74可作为临床预防和治疗肺癌的候选靶标。