Infiltrating bone marrow mesenchymal stem cells (BM-MSCs) increase prostate cancer cell invasion via altering the CCL5/HIF2α/androgen receptor signals.
Infiltrating bone marrow mesenchymal stem cells (BM-MSCs) increase prostate cancer cell invasion via altering the CCL5/HIF2α/androgen receptor signals.
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浸润骨髓间充质干细胞（BM-MSC）通过改变CCL5/HIF2α/雄激素受体信号来增加前列腺癌细胞的侵袭。
DOI：
10.18632/oncotarget.4515
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Chang C
中科院分区：
文献类型：
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作者：
Luo J;Lee SO;Cui Y;Yang R;Li L;Chang C
肿瘤微环境中的几种浸润细胞通过分泌多种细胞因子影响肿瘤的进展。本研究发现，从BM-MSCs分泌的CCL5通过增强前列腺癌（PCa）细胞中缺氧诱导因子2α (HIF2α)的表达来抑制雄激素受体（AR）信号。机制解剖表明，HIF2α的升高可能改变AR- hsp90的相互作用，抑制AR的转激活，抑制HIF2α逆转了bm - mscs增加的PCa干细胞群和PCa细胞的侵袭。重要的是，CCL5可以抑制脯氨酸羟化酶（PHDs）的表达，从而抑制vhl介导的HIF2α泛素化。综上所述，这些结果表明CCL5信号从浸润的BM-MSC细胞到PCa细胞内的HIF2α信号可能通过改变AR信号在增加PCa干细胞数量和PCa转移中起关键作用。靶向这一新发现的CCL5/HIF2α/AR轴信号轴可能使我们开发出一种抑制PCa转移的新途径。
Several infiltrating cells in the tumor microenvironment could influence the cancer progression via secreting various cytokines. Here, we found the CCL5 secreted from BM-MSCs suppressed androgen receptor (AR) signals via enhancing the expression of hypoxia inducible factor 2α (HIF2α) in prostate cancer (PCa) cells. Mechanism dissection revealed that the increased HIF2α might alter the AR-HSP90 interaction to suppress the AR transactivation, and inhibition of HIF2α reversed the BM-MSCs-increased PCa stem cell population and PCa cells invasion. Importantly, CCL5 could suppress the prolyl hydroxylases (PHDs) expression, which might then lead to suppress VHL-mediated HIF2α ubiquitination. Together, these results demonstrated that the CCL5 signals from infiltrating BM-MSC cells to HIF2α signals within PCa cells might play a key role to increase PCa stem cell population and PCa metastasis via altering the AR signals. Targeting this newly identified CCL5/HIF2α/AR axis signal axis may allow us to develop a novel way to suppress PCa metastasis.