Activation of STAT3 is a key event in TLR4 signaling-mediated melanoma progression

被引:52
作者
Fu Xiu-Qiong [1 ,2 ,3 ]
Liu Bin [1 ]
Wang Ya-Ping [1 ,2 ]
Li Jun-Kui [1 ,2 ]
Zhu Pei-Li [1 ,2 ,3 ]
Li Ting [1 ]
Tse Kai-Wing [1 ]
Chou Ji-Yao [1 ,2 ]
Yin Cheng-Le [1 ,2 ]
Bai Jing-Xuan [1 ,2 ]
Liu Yu-Xi [1 ,2 ]
Chen Ying-Jie [1 ,2 ]
Yu Zhi-Ling [1 ,2 ,3 ,4 ]
机构
[1] Hong Kong Baptist Univ, Ctr Canc & Inflammat Res, Sch Chinese Med, Hong Kong, Peoples R China
[2] Hong Kong Baptist Univ, Consun Chinese Med Res Ctr Renal Dis, Hong Kong, Peoples R China
[3] HKBU Shenzhen Res Inst & Continuing Educ, Res & Dev Ctr Nat Hlth Prod, Shenzhen, Peoples R China
[4] Hong Kong Baptist Univ, JaneClare Transdermal TCM Therapy Lab, Hong Kong, Peoples R China
关键词
MONOPHOSPHORYL-LIPID-A; TOLL-LIKE RECEPTORS; CELLS; PARTHENOLIDE; PROMOTES; TRANSCRIPTION; EXPRESSION; CANCER; INFLAMMATION; METASTASIS;
D O I
10.1038/s41419-020-2440-1
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Malignant melanoma is aggressive and has a high mortality rate. Toll-like receptor 4 (TLR4) has been linked to melanoma growth, angiogenesis and metastasis. However, signal transduction mediated by TLR4 for driving melanoma progression is not fully understood. Signal transducer and activator of transcription 3 (STAT3) has been identified as a major oncogene in melanoma progression. We found: that TLR4 expression positively correlates with activation/phosphorylation of STAT3 in human melanoma samples; that TLR4 ligands activate STAT3 through MYD88 and TRIF in melanoma cells; and that intratumoral activation of TLR4 increases STAT3 activation in the tumor and promotes tumor growth, angiogenesis, epithelial-mesenchymal transition (EMT) and the formation of an immunosuppressive tumor microenvironment in mice. Further, we found that the effects mediated by activating TLR4 are weakened by suppressing STAT3 function with a dominant negative STAT3 variant in melanoma. Collectively, our work identifies STAT3 activation as a key event in TLR4 signaling-mediated melanoma progression, shedding new light on the pathophysiology of melanoma.
引用
收藏
页数:15
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