Infiltrating T cells promote prostate cancer metastasis via modulation of FGF11→miRNA-541→androgen receptor (AR)→MMP9 signaling.
Infiltrating T cells promote prostate cancer metastasis via modulation of FGF11→miRNA-541→androgen receptor (AR)→MMP9 signaling.
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DOI：
10.1016/j.molonc.2014.07.013
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发表时间：
2015-01
影响因子：
6.6
通讯作者：
Chang C
中科院分区：
文献类型：
--
作者：
Hu S;Li L;Yeh S;Cui Y;Li X;Chang HC;Jin J;Chang C
早期的临床研究表明，浸润性T细胞可能与前列腺癌(PCa)患者的不良预后有关。然而，T细胞如何促进前列腺癌进展的详细机制仍不清楚。在这里，我们发现前列腺癌细胞通过分泌更多的趋化因子-CXCL9，比周围的正常前列腺细胞有更好的能力招募更多的CD4(+)T细胞。更多的CD4(+)T细胞招募到PCa的后果可能会导致PCa细胞侵袭的增强。机制剖析表明，浸润性→(+)T细胞可能通过调节FGF11miRNA541信号抑制PCa雄激素受体(AR)信号发挥作用。被抑制的AR信号可能会改变MMP9信号，从而促进PCa细胞的侵袭。重要的是，通过AR-siRNA或抗雄激素恩扎鲁塔胺抑制的AR信号在PCa细胞中也促进了T细胞的募集，这种正反馈调节的结果可以增强PCa细胞的侵袭。通过FGF11-siRNA、miRNA-541抑制剂或MMP9抑制剂靶向这些新发现的信号，均可部分逆转增强的PCa细胞侵袭。体内小鼠模型的结果也证实了共培养研究中的体外细胞系。以上结果提示，CD4(+)T细胞可通过调节FGF11miRNA-541FGF11miRNA541AR→MMP9信号通路促进PCa转移。靶向这些新发现的信号可能为我们提供一种新的潜在的治疗方法来更好地对抗前列腺癌转移。
Early clinical studies suggested infiltrating T cells might be associated with poor outcomes in prostate cancer (PCa) patients. The detailed mechanisms how T cells contribute to PCa progression, however, remained unclear. Here, we found PCa cells have a better capacity to recruit more CD4(+) T cells than the surrounding normal prostate cells via secreting more chemokines-CXCL9. The consequences of more recruited CD4(+) T cells to PCa might then lead to enhance PCa cell invasion. Mechanism dissection revealed that infiltrating CD4(+) T cells might function through the modulation of FGF11→miRNA-541 signals to suppress PCa androgen receptor (AR) signals. The suppressed AR signals might then alter the MMP9 signals to promote the PCa cell invasion. Importantly, suppressed AR signals via AR-siRNA or anti-androgen Enzalutamidein PCa cells also enhanced the recruitment of T cells and the consequences of this positive feed back regulation could then enhance the PCa cell invasion. Targeting these newly identified signals viaFGF11-siRNA, miRNA-541 inhibitor or MMP9 inhibitor all led to partially reverse the enhanced PCa cell invasion. Results from in vivo mouse models also confirmed the in vitro cell lines in co-culture studies. Together, these results concluded that infiltrating CD4(+) T cells could promote PCa metastasis via modulation of FGF11→miRNA-541→AR→MMP9 signaling. Targeting these newly identified signals may provide us a new potential therapeutic approach to better battle PCa metastasis.
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影响因子：
9
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影响因子：
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