Role of the overexpression of TRAF4 in predictingthe prognosis of intrahepatic cholangiocarcinoma

Abstract

The incidence of intrahepatic cholangiocarcinoma (ICC) is progressively increasing worldwide, and its prognosis remains poor. Accumulating evidence has demonstrated that tumor necrosis factor receptor-associated factor 4 (TRAF4), an adaptor protein, is involved in the carcinogenesis and progression of several tumor types. However, the function of TRAF4 in predicting prognosis, and mediating migration and invasion of ICC remains to be elucidated. In the present study, immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to determine that the expression of TRAF4 at the mRNA and protein levels in ICC tissues was significantly higher compared with that in non‑tumor tissues. The overexpression of TRAF4 was positively correlated with poor differentiation, regional lymphatic metastasis, and high tumor‑node-metastasis staging. Inhibiting the expression of TRAF4 using small interfering RNA decreased the migration and invasion of ICC cells in vitro. In addition, the AKT inhibitor perifosine eliminated the effect of TRAF4 on the invasion and migration of ICC cells in vitro. Clinically, the overexpression of TRAF4 was correlated with shorter overall survival rate and elevated recurrence rate in patients with ICC. Furthermore, patients with ICC with a high expression of TRAF4 and lymphatic metastasis were closely associated with a poorer prognosis compared with the other groups. Multivariate analysis indicated that the overexpression of TRAF4 was an independent prognostic indicator for patients with ICC. It was identified that a high level of TRAF4 facilitated the invasiveness of ICC cells via the activation of AKT signaling. The overexpression of TRAF4 may be a prognostic biomarker and candidate therapeutic target for patients with ICC.

YY1-induced lncRNA ZFPM2-AS1 facilitates cell proliferation and invasion in small cell lung cancer via upregulating of TRAF4

“…As expected, ZFPM2-AS1 could sponge miR-3612 to release TRAF4 expression. Moreover, the tumor-facilitator role of TRAF4 has been validated in hepatocellular carcinoma [34], intrahepatic cholangiocarcinoma [35], breast cancer [36], and colon cancer [37]. More importantly, TRAF4 is confirmed to promote the development of lung cancer [38][39][40].…”

LncRNA SNHG15 regulates osteosarcoma progression in vitro and in vivo via sponging miR-346 and regulating TRAF4 expression

“…Evidence is increasingly supporting that some miRNAs exert a tumor-suppressing role through targeting and inhibiting the expression of multiple oncogenes. The oncogene TRAF4 has been widely studied in a variety of cancers, such as hepatocellular carcinoma [32] cholangiocarcinoma [33], and non-small cell lung cancer [34]. Kang et al showed that TRAF4 was upregulated in cholangiocarcinoma tissues and positively correlated with tumor differentiation and TNM (Tumor, Lymph Node, Metastasis) stage [33].…”

“…The oncogene TRAF4 has been widely studied in a variety of cancers, such as hepatocellular carcinoma [32] cholangiocarcinoma [33], and non-small cell lung cancer [34]. Kang et al showed that TRAF4 was upregulated in cholangiocarcinoma tissues and positively correlated with tumor differentiation and TNM (Tumor, Lymph Node, Metastasis) stage [33]. Yang et al showed that the level of TRAF4 mRNA was inversely correlated with miR-302c-3p expression in hepatocellular carcinoma specimens, and TRAF4 restoration reversed the inhibitory effect of miR-302c-3p on AKT-induced EMT and hepatocellular carcinoma cell metastasis [32].…”

“…Yang et al showed that the level of TRAF4 mRNA was inversely correlated with miR-302c-3p expression in hepatocellular carcinoma specimens, and TRAF4 restoration reversed the inhibitory effect of miR-302c-3p on AKT-induced EMT and hepatocellular carcinoma cell metastasis [32]. It has been reported that the upregulated TRAF4 was present in cholangiocarcinoma [33]. Consistent with the previous reports, the expression level of TRAF4 was promoted in OS tissues at both mRNA and protein levels in our study.…”

Roles of TRAFs in Ischemia-Reperfusion Injury

“…Perhaps due to the particularity of its structure and expression, TRAF4 plays an important role in developmental steps, such as tracheal ring formation, neural tube closure, and axial skeleton formation (Kim E. et al, 2017). However, there were no obvious immunological defects or lymphocyte changes in TRAF4-deficient mice (Kang et al, 2018), suggesting that TRAF4 may not have a significant impact on immune function in mice. Moreover, although researchers have confirmed that TRAF4 did not bind to TNF receptors, or only weakly interacted with a few TNF receptor family members under certain conditions (Ren et al, 2015), TRAF4 is a crucial regulator in the transforming growth factor-β (TGF-β), Wnt-β-catenin, and phosphatidylinositol-3-kinase (PI3K)/AKT pathways, which are involved in tumorigenesis and progression (Kang et al, 2018).…”