Invasive Fusobacterium nucleatum activates beta-catenin signaling in colorectal cancer via a TLR4/P-PAK1 cascade.
Invasive Fusobacterium nucleatum activates beta-catenin signaling in colorectal cancer via a TLR4/P-PAK1 cascade.
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DOI：
10.18632/oncotarget.15992
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发表时间：
2017-05-09
期刊：
影响因子：
--
通讯作者：
Fu X
中科院分区：
文献类型：
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作者：
Chen Y;Peng Y;Yu J;Chen T;Wu Y;Shi L;Li Q;Wu J;Fu X
具核梭杆菌（Fn）在结直肠癌（CRC）发生中的潜在机制知之甚少。在此，我们检测了CRC组织中Fn的丰度，以及Fn阳性和Fn阴性CRC中β-连环蛋白、TLR 4和PAK 1蛋白的丰度。此外，我们从CRC组织中分离了一株Fn（F01），并检查了Fn（F01）感染结肠癌细胞是否通过TLR 4/P-PAK 1/β-连环蛋白S675级联激活β-连环蛋白信号传导。62.2%的结直肠癌组织中富含侵袭性Fn。Fn阳性的CRC中TLR 4、PAK 1和β-catenin蛋白的表达量明显高于Fn阴性的CRC（P < 0.05）。Fn及其脂多糖诱导TLR 4/P-PAK 1/P-β-catenin S675/C-myc/CyclinD 1蛋白丰度显著增加，以及β-catenin核转位。此外，在用Fn攻击之前抑制TLR 4或PAK 1显著降低P-β-catenin S675、C-myc和Cyclin D1的蛋白丰度，以及核β-catenin积累。TLR 4的抑制显著降低了P-PAK 1蛋白的丰度，并且我们首次使用免疫沉淀法观察到TLR 4和P-PAK 1之间的相互作用。我们的数据表明，侵袭性Fn通过TLR 4/P-PAK 1/β-catenin S675级联激活CRC中的β-catenin信号传导。此外，TLR 4和PAK 1可能是治疗Fn相关CRC的潜在药物靶点。
The underlying mechanism of Fusobacterium nucleatum (Fn) in the carcinogenesis of colorectal cancer (CRC) is poorly understood. Here, we examined Fn abundance in CRC tissues, as well as β-catenin, TLR4 and PAK1 protein abundance in Fn positive and Fn negative CRCs. Furthermore, we isolated a strain of Fn (F01) from a CRC tissue and examined whether Fn (F01) infection of colon cancer cells activated β-catenin signaling via the TLR4/P-PAK1/P-β-catenin S675 cascade. Invasive Fn was abundant in 62.2% of CRC tissues. TLR4, PAK1 and nuclear β-catenin proteins were more abundant within Fn-positive over Fn-negative CRCs (P < 0.05). Fn and its lipopolysaccharide induced a significant increase in TLR4/P-PAK1/P-β-catenin S675/C-myc/CyclinD1 protein abundance, as well as in the nuclear translocation of β-catenin. Furthermore, inhibition of TLR4 or PAK1 prior to challenge with Fn significantly decreased protein abundance of P-β-catenin S675, C-myc and Cyclin D1, as well as nuclear β-catenin accumulation. Inhibition of TLR4 significantly decreased P-PAK1 protein abundance, and for the first time, we observed an interaction between TLR4 and P-PAK1 using immunoprecipitation. Our data suggest that invasive Fn activates β-catenin signaling via a TLR4/P-PAK1/P-β-catenin S675 cascade in CRC. Furthermore, TLR4 and PAK1 could be potential pharmaceutical targets for the treatment of Fn-related CRCs.