CXCL12/SDF-1 alpha 通过 Carma3/Bcl10/Malt1 复合物激活 NF-kappaB 并促进口腔癌侵袭。
CXCL12/SDF-1 alpha activates NF-kappaB and promotes oral cancer invasion through the Carma3/Bcl10/Malt1 complex.
机构信息
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, CA 90095-1668, USA.
出版信息
Int J Oral Sci. 2009 Sep;1(3):105-18. doi: 10.4248/IJOS.09059.
AIM
To determine how SDF-1 alpha/CXCR4 activates nuclear factor-kappa B (NF-kappaB) and promotes oral squamous cell carcinoma (OSCC) invasion.
METHODOLOGY
A lentivirus-based knockdown approach was utilized to deplete gene expression. NF-kappaB activation was evaluated by Western blot analysis and electrophoretic mobility shift (EMSA).
RESULTS
We show that the activation of NF-kappaB by CXCR4 occurs through the Carma3/Bcl10/Malt1 (CBM) complex in OSCC. We found that loss of components of the CBM complex in HNSCC can inhibit SDF-1 alpha induced phosphorylation and degradation of IkappaBalpha, while TNF alpha induced IKK activation remains unchanged. Further, we identified a role for novel and atypical, but not classical, PKCs in activating IKK through CXCR4. Importantly, inhibition of the CBM complex leads to a significant decrease in SDF-1 alpha mediated invasion of OSCC.
CONCLUSION
The CBM complex plays a critical role in CXCR4-induced NF-kappaB activation in OSCC. Targeting molecular components of the NF-kappaB signaling pathway may provide an important therapeutic opportunity in controlling the progression and metastasis of OSCC mediated by SDF-1 alpha.
目的
确定 SDF-1α/CXCR4 如何激活核因子-κB（NF-κB）并促进口腔鳞状细胞癌（OSCC）侵袭。
方法
利用基于慢病毒的敲低方法来耗尽基因表达。通过 Western blot 分析和电泳迁移率变动（EMSA）评估 NF-κB 激活。
结果
我们表明，CXCR4 通过 Carma3/Bcl10/Malt1（CBM）复合物激活 NF-κB。我们发现，HNSCC 中 CBM 复合物成分的缺失可抑制 SDF-1α诱导的 IkappaBalpha 的磷酸化和降解，而 TNFα诱导的 IKK 激活保持不变。此外，我们确定了 novel 和 atypical，但不是 classical，PKC 在通过 CXCR4 激活 IKK 中的作用。重要的是，抑制 CBM 复合物可导致 SDF-1α介导的 OSCC 侵袭显著减少。
结论
CBM 复合物在 OSCC 中 CXCR4 诱导的 NF-κB 激活中起关键作用。靶向 NF-κB 信号通路的分子成分可能为控制 SDF-1α 介导的 OSCC 进展和转移提供重要的治疗机会。
Zotero 插件