Expression of TWEAK/Fn14 in neuroblastoma: Implications in tumorigenesis
Expression of TWEAK/Fn14 in neuroblastoma: Implications in tumorigenesis
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DOI：
10.3892/ijo.2013.1800
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发表时间：
2013-04-01
影响因子：
5.2
通讯作者：
Sveinbjornsson, Baldur
中科院分区：
文献类型：
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作者：
Pettersen, Ingvild;Baryawno, Ninib;Sveinbjornsson, Baldur
肿瘤坏死因子样细胞凋亡弱诱导剂（TWEAK）是肿瘤坏死因子（TNF）细胞因子家族的一员，通过结合细胞表面受体Fn14作用于应答细胞。TWEAK结合Fn14受体或组成型Fn14过表达已被证明可激活核因子κ B信号，这在肿瘤发生和癌症治疗抵抗中很重要。在本研究中，我们证明了TWEAK和Fn14在神经母细胞瘤细胞系和原发肿瘤中表达，并且在高分期肿瘤中均观察到其表达水平升高。体外用重组TWEAK治疗神经母细胞瘤细胞系可提高其存活率，其部分原因是NF-kappa B信号的激活。此外，TWEAK诱导神经母细胞瘤细胞中基质金属蛋白酶9 （matrix metalloprotease-9, MMP-9）的释放，提示TWEAK可能在神经母细胞瘤发生的侵袭期发挥作用。通过siRNA沉默TWEAK和Fn14基因功能，可显著降低TWEAK诱导的细胞存活率。因此，TWEAK和Fn14在神经母细胞瘤中的表达表明，TWEAK是原发性神经母细胞瘤生长、侵袭和存活的重要调节因子，对TWEAK/Fn14通路进行治疗干预可能是神经母细胞瘤治疗的重要临床策略。
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF) family of cytokines, acts on responsive cells via binding to a cell surface receptor called Fn14. TWEAK binding to an Fn14 receptor or constitutive Fn14 overexpression has been shown to activate nuclear factor kappa B signaling which is important in tumorigenesis and cancer therapy resistance. In the present study, we demonstrate that TWEAK and Fn14 are expressed in neuroblastoma cell lines and primary tumors, and both are observed at increased levels in high-stage tumors. The treatment of neuroblastoma cell lines with recombinant TWEAK in vitro causes increased survival, and this effect is partially due to the activation of NF-kappa B signaling. Moreover, TWEAK induces the release of matrix metalloprotease-9 (MMP-9) in neuroblastoma cells, suggesting that TWEAK may play a role in the invasive phase of neuroblastoma tumorigenesis. TWEAK-induced cell survival was significantly reduced by silencing the TWEAK and Fn14 gene functions by siRNA. Thus, the expression of TWEAK and Fn14 in neuroblastoma suggests that TWEAK functions as an important regulator of primary neuroblastoma growth, invasion and survival and that the therapeutic intervention of the TWEAK/Fn14 pathway may be an important clinical strategy in neuroblastoma therapy.