Triggering of Toll-like receptor 4 on metastatic breast cancer cells promotes αvβ3-mediated adhesion and invasive migration
Triggering of Toll-like receptor 4 on metastatic breast cancer cells promotes αvβ3-mediated adhesion and invasive migration
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DOI：
10.1007/s10549-011-1844-0
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发表时间：
2012-06-01
影响因子：
3.8
通讯作者：
Feng, Zuo-Hua
中科院分区：
文献类型：
--
作者：
Liao, Sheng-Jun;Zhou, Yuan-Hong;Feng, Zuo-Hua
已经发现触发肿瘤细胞上的Toll样受体4（TLR 4）通过促进肿瘤细胞增殖和存活来促进肿瘤进展。然而，到目前为止，TLR 4信号转导对肿瘤转移的影响尚未得到很好的阐明。在这里，我们报告，触发TLR 4对转移性乳腺癌细胞可以间接调节α v β 3的表达和TPM 1和maspin的表达，并促进α v β 3介导的粘附和侵袭性迁移的细胞。在转移性乳腺癌细胞中，TLR 4信号通过激活NF-κ B增加整合素α v β 3的表达，导致肿瘤细胞对α v β 3配体的粘附能力增加，以及肿瘤细胞中肌动蛋白的聚合和MMP-9的产生增加以响应ECM。HoxD 3是NF-κ B B上调α v和β 3表达所必需的。此外，TLR 4信号通过激活NF-κ B增加乳腺癌细胞中miR-21的表达。相应地，TPM 1和maspin的表达在蛋白水平上降低，而这些基因的转录活性不受影响。与对α v β 3介导的粘附和侵袭性迁移的促进作用一致，TLR 4信号传导促进了转移性乳腺癌细胞在循环中和侵袭后的停滞。抑制NF-κ B B可阻断TLR 4信号通路的作用。这些结果表明，转移性乳腺癌细胞可以获得更高的转移潜能，由于触发TLR 4和NF-κ B B在细胞中的激活，并且TLR 4和NF-κ B B都可以作为预防乳腺癌细胞转移的治疗靶点。
Triggering of Toll-like receptor 4 (TLR4) on tumor cells has been found to promote tumor progression by promoting tumor cell proliferation and survival. So far, however, the effect of TLR4 signaling on tumor metastasis has not been well elucidated. Here, we report that triggering of TLR4 on metastatic breast cancer cells could reciprocally regulate the expression of alpha v beta 3 and the expressions of TPM1 and maspin, and promote alpha v beta 3-mediated adhesion and invasive migration of the cells. In metastatic breast cancer cells, TLR4 signaling increased the expression of integrin alpha v beta 3 by activating NF-kappa B, resulting in the increased adhesion capacity of tumor cells to the ligand for alpha v beta 3, and the increased polymerization of actin and production of MMP-9 in tumor cells in response to ECM. HoxD3 was required for the up-regulation of alpha v and beta 3 expressions by NF-kappa B. Moreover, TLR4 signaling increased the expression of miR-21 in breast cancer cells by activating NF-kappa B. Accordingly, the expressions of TPM1 and maspin were decreased at protein level, whereas the transcription activity of these genes was not influenced. Consistent with the promoting effect on alpha v beta 3-mediated adhesion and invasive migration, TLR4 signaling promoted the arrest of metastatic breast cancer cells in circulation and following invasion. The effect of TLR4 signaling could be abrogated by inhibiting NF-kappa B. These findings suggest that metastatic breast cancer cells could acquire higher metastatic potential due to triggering of TLR4 and activation of NF-kappa B in the cells, and that both TLR4 and NF-kappa B could be therapeutic targets for preventing metastasis of breast cancer cells.