TRAF4 Enhances Osteosarcoma Cell Proliferation and Invasion by Akt Signaling Pathway

Abstract

TRAF4, or tumor necrosis factor receptor-associated factor 4, is overexpressed in several cancers, suggesting a specific role in cancer progression. However, its functions in osteosarcoma are unclear. This study aimed to explore the expression of TRAF4 in osteosarcoma tissues and cells, the correlation of TRAF4 to clinical pathology of osteosarcoma, as well as the role and mechanism of TRAF4 in osteosarcoma metastasis. The protein expression levels of TRAF4 in osteosarcoma tissues and three osteosarcoma cell lines, MG-63, HOS, and U2OS, were assessed. Constructed TRAF4 overexpression vectors and established TRAF4 overexpression of the U2OS cell line. Cell proliferation, cell invasion, protein levels, and TRAF4 phosphorylations were assessed following TRAF4 transfection, as well as the effects of TRAF4 siRNA on cell proliferation and invasion. The results show that TRAF4 protein levels in osteosarcoma tissues were significantly higher than that in normal bone tissues. Importantly, an obvious upregulation of TRAF4 was found in carcinoma tissues from patients with lung metastasis compared with patients without lung metastasis. Consistently, a similar increase in TRAF4 mRNA and protein was also demonstrated in the osteosarcoma cell lines MG-63, HOS, and U2OS compared to normal bone cells, hFOB1.19. When TRAF4 was overexpressed in U2OS cells, cell proliferation was significantly enhanced, accompanied by an increase in Ki67 expression and colony formation. Compared with the control and vector-treated groups, TRAF4 transfection increased the invasion potential of U2OS cells (p < 0.05). Interestingly, TRAF4 transfection significantly enhanced the phosphorylation of Akt. After blocking Akt with its specific siRNA, TRAF4-induced cell proliferation and invasion were dramatically attenuated. In summary, our findings demonstrated that TRAF4 enhances osteosarcoma cell proliferation and invasion partially by the Akt pathway. This work suggests that TRAF4 might be an important target in osteosarcoma.

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

“…The results of the present study demonstrated that inhibition of the expression of TRAF4 using siRNA in RBE and HCCC9810 cells impaired their motility and invasiveness of capabilities. Mechanistically, it was found that the downregulation of TRAF4 in ICC cells significantly inhibited the activation of AKT signaling in vitro, similarly consistent with previous studies (21,24). Furthermore, the AKT inhibitor perifosine eradicated the effect of TRAF4 on the ICC cells.…”

“…It was previously reported that the upregulation of TRAF4 increased the mobility and invasiveness of HCC cells in vivo and in vitro, and increased the level of the transcription factor slug, which acts as a key inducer of the EMT process, via activation of the PI3K/AKT signaling pathway (21). Yao et al (24) showed that TRAF4 fosters AKT membrane recruitment and, crucially, binds directly to AKT to promote the proliferation and invasion of breast cancer cells. In addition, TRAF4 directly interacts with TGF-β protein, and enhances TGF-β-induced small mothers against decapentaplegic (SMAD) and non-SMAD signaling to drive breast cancer metastasis (22).…”

“…The overexpression of TRAF4 has been verified in numerous types of cancer, including breast cancer, hepatocellular carcinoma, lung cancer and colon cancer (18)(19)(20)(21). Several studies have reported that TRAT4 is crucial in a number of signaling pathways involved in tumorigenesis and progression, including phosphatidylinositol-3-kinase (PI3K)/AKT, transforming growth factor-β (TGF-β), NF-κB and Wnt-β-catenin (21)(22)(23)(24). However, the role of TRAF4 in the progression of ICC remains to be elucidated.…”

S‐Adenosylmethionine Affects ERK1/2 and Stat3 Pathways and Induces Apotosis in Osteosarcoma Cells

“…The human osteosarcoma U2OS cell line is a well-established and widely used model system of osteosarcoma cells (Lucero et al, 2013;Spina et al, 2013a;Yao et al, 2014).…”

Molecular pathogenesis and therapeutic strategies of human osteosarcoma

“…Upregulation of the former has been significantly implicated in OS pathogenesis, resulting in increased proliferation, increased invasion, and decreased apoptosis of tumor cells [90] . Researchers have shown that various molecules cause this activation, including the long noncoding RNA metastasis-associated Current status of osteosarcoma biology and therapy lung adenocarcinoma transcript 1 (MALAT1), tumor necrosis factor receptor-associated factor 4 (TRAF 4), and autophagy related protein 6 (Beclin-1) [91][92][93] . Furthermore, suppressing such activation may not only be involved in decreasing the aggressiveness of tumors, but may also be involved in overcoming chemoresistance, further demonstrating the importance of PI3K/ AKT signaling as a therapeutic target [91,[94][95][96][97] .…”