Abstract
Although TNFAIP8 overexpression has been implicated in several human cancers, its clinical significance and biological function in hepatocellular carcinoma (HCC) remains unknown. Our study demonstrated that TNFAIP8 overexpression in primary HCC samples correlated with TNM stage, recurrence, poor prognosis and served as an independent favorable prognostic factor. We further showed that TNFAIP8 upregulated cell proliferation, migration, invasion and xenograft tumor growth of HCC cells. In addition, TNFAIP8 overexpression inhibited YAP phosphorylation, increased its nuclear localization and stabilization, leading to upregulation of cyclin proteins, CTGF and cell proliferation. We also found that TNFAIP8 could interact with LATS1 and decreased its phosphorylation. Depletion of LATS1 and YAP by siRNA blocked the biological effects of TNFAIP8. Collectively, the present study provides a novel finding that TNFAIP8 promotes HCC progression through LATS1-YAP signaling pathway. TNFAIP8 may serve as a candidate biomarker for poor prognosis and a target for new therapies.
Highlights
Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide and the incidence of this cancer is increasing [1]
Expression of TNFAIP8 correlates with clinicopathological factors and poor prognosis in HCC patients
We find out a new Hippo regulator, which interacts with LATS1 and inhibits its phosphorylation, leading to nuclear accumulation of YAP
Summary
Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide and the incidence of this cancer is increasing [1]. Many molecular markers that affect aggressiveness of HCC [5,6,7,8]. It is important to identify new markers and their molecular mechanisms involved in the regulation of HCC aggressiveness. The Hippo signaling pathway promotes contact inhibition of cell growth and inducces of apoptosis [9, 10]. Dysregulation of Hippo signaling pathway has been indicated in hepatocellular carcinoma [11, 12]. Loss of Hippo signaling leads to YAP nuclear accumulation and eventually liver tumor in a transgenic mouse model [13]. Hippo effector YAP is overexpressed in various cancers and functions as an oncogene [14,15,16,17,18]
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