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Dishevelled Associated Activator Of Morphogenesis (DAAM) Facilitates Invasion of Hepatocellular Carcinoma by Upregulating Hypoxia-Inducible Factor 1α (HIF-1α) Expression

Xiaoxu Fang, Dandan Zhang, Wei Zhao, Longfei Gao, Lanping Wang

Gastrointestinal Department, YIDU Central Hospital, Weifang, Shandong, China (mainland)

Med Sci Monit 2020; 26:e924670

DOI: 10.12659/MSM.924670

Available online: 2020-06-12

Published: 2020-08-09

BACKGROUND: The dishevelled associated activator of morphogenesis (DAAM) family, consisting of DAAM1 and DAAM2, is an important component of the Wnt signal pathway. Previous studies have suggested that DAAM2 reduces Von Hippel-Lindau (VHL) expression by promoting its ubiquitination, but the correlation between DAAM and HIF-1alpha in hepatocellular carcinoma (HCC) has not been studied.
MATERIAL AND METHODS: In our study, expression of DAAM1 and DAAM2 in HCCs and tumor-adjacent liver tissues was assessed with qRT-PCR and immunohistochemistry. Correlations between DAAM1/2 and the clinicopathologic variables were evaluated with the Chi-square test. With univariate and multivariate analysis, we further evaluated the prognostic significance of DAAM1 and DAAM2. Using in vitro experiments, we assessed the functions of DAAM1 and DAAM2 in invasion and proliferation in different HCC cell lines and investigated their underlying mechanisms.
RESULTS: DAAM1 and 2 overexpression were 18.8% and 48.7%, respectively, of the whole cohort. mRNAs of DAAM2 in HCCs were substantially higher than mRNAs in liver tissues, while DAAM1 mRNA had no marked difference. High DAAM2 expression was notably associated with advanced T stage (P=0.032), TNM stage (P=0.032), and overall survival (OS) rate (P=0.004). DAAM 2 knockdown promoted VHL accumulation and subsequent HIF-1alpha down-regulation in HCC cells. In HCC specimens, DAAM2 expression was also negatively correlated with VHL and positively associated with HIF-1alpha. Moreover, HIF-1alpha was required in DAAM2-induced invasion of HCC cells.
CONCLUSIONS: DAAM2, rather than DAAM1, was able to predict prognosis of HCC. DAAM2 decreased VHL expression and consequently upregulated HIF-1alpha, eventually facilitating invasion of HCC.

Keywords: Carcinoma, Hepatocellular, Cell Hypoxia, Neoplasm Invasiveness, Prognosis, Wnt Signaling Pathway