Zhang Xu, Wu Lisha, Xiao Ta, Tang Ling, Jia Xuekun, Guo Yeye, Zhang JiangLin, Li Jie, He Yijing, Su Juan, Zhao Shuang, Tao Juan, Zhou Jianda, Chen Xiang, Peng Cong
The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Oncogenesis. 2018 Feb 20;7(2):17. doi: 10.1038/s41389-018-0030-1.
TRAF6, a well-known adapter molecule, plays pivotal role in TLR/IL-1R associated signaling pathway. Although TRAF6 has been shown to have oncogenic activity in various malignant tumors, the details remain unclear. In this study, we demonstrated that TRAF6 facilitates Ras (G12V) and EGF-induced cellular transformation through EGFR. Silencing of TRAF6 expression significantly downregulated AP-1 activity, as well as MMP-2,9 expression after EGF stimulation. Furthermore, we found that TRAF6 plays an essential role in cutaneous squamous cell carcinoma (cSCC) malignant phenotypes, affecting cell growth and migration. CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is over-expressed in tumors and induces tumorigenesis. Our results showed that CD147 formed complex with EGFR and TRAF6. Knockdown of TRAF6 disrupted the CD147-EGFR complex, thereby inducing EGFR endocytosis. Therefore, TRAF6 might be a novel molecular target for cSCC prevention or therapy.
TRAF6是一种著名的衔接分子，在TLR/IL-1R相关信号通路中起关键作用。尽管TRAF6已被证明在各种恶性肿瘤中具有致癌活性，但其具体细节仍不清楚。在本研究中，我们证明TRAF6通过表皮生长因子受体（EGFR）促进Ras（G12V）和表皮生长因子（EGF）诱导的细胞转化。TRAF6表达的沉默显著下调了AP-1活性以及EGF刺激后基质金属蛋白酶-2、9的表达。此外，我们发现TRAF6在皮肤鳞状细胞癌（cSCC）的恶性表型中起重要作用，影响细胞生长和迁移。CD147/基底膜蛋白是一种属于免疫球蛋白超家族的跨膜糖蛋白，在肿瘤中过度表达并诱导肿瘤发生。我们的结果表明，CD147与EGFR和TRAF6形成复合物。敲低TRAF6会破坏CD147-EGFR复合物，从而诱导EGFR内吞作用。因此，TRAF6可能是cSCC预防或治疗的一个新的分子靶点。
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