RET Signaling in Prostate Cancer.
RET Signaling in Prostate Cancer.
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DOI：
10.1158/1078-0432.ccr-17-0528
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发表时间：
2017-08-15
期刊：
影响因子：
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通讯作者：
Ittmann M
中科院分区：
文献类型：
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作者：
Ban K;Feng S;Shao L;Ittmann M
大直径神经周围前列腺癌与不良预后相关。GDNF与其共受体GFRα1结合RET并激活下游原癌信号传导。由于GDNF和GFRα1都是由神经分泌的，我们研究了RET信号在前列腺癌中的作用。评估RET、GDNF和/或GFRα1的表达。测定RET信号传导对体内增殖、侵袭和软琼脂集落形成、神经周围侵袭和生长的影响。通过蛋白质印迹法检查RET下游的细胞信号传导。RET在所有前列腺癌细胞系中表达。GFRα1仅在22 Rv 1细胞中表达，这是唯一对外源性GDNF有反应的细胞系。相反，所有细胞系都对GDNF加GFRα1有反应。背根神经节的条件培养基含有分泌的GFRα1并促进转化相关表型，其可被抗GFR α1抗体阻断。在背根神经节试验中，抗GFR α抗体和RET敲低可抑制神经周侵袭。在体内，RET的敲低抑制肿瘤生长。RET信号激活ERK或AKT信号依赖于上下文，但磷酸化的p70 S6激酶在所有情况下显着增加。p70 S6激酶的敲低显著降低RET诱导的转化表型。最后，RET在18%的腺癌和所有三种检查的小细胞癌中表达。RET通过激活p70 S6激酶促进转化相关表型，包括前列腺癌的神经浸润。由神经分泌的GFRα1是RET信号传导的限制因子，产生了RET信号传导可能发生的神经周小生境。
Large diameter perineural prostate cancer is associated with poor outcomes. GDNF, with its co-receptor GFRα1, binds RET and activates downstream pro-oncogenic signaling. Since both GDNF and GFRα1 are secreted by nerves, we examined the role of RET signaling in prostate cancer. Expression of RET, GDNF and/or GFRα1 was assessed. The impact of RET signaling on proliferation, invasion and soft agar colony formation, perineural invasion and growth in vivo was determined. Cellular signaling downstream of RET was examined by Western blotting. RET is expressed in all prostate cancer cell lines. GFRα1 is only expressed in 22Rv1 cells, which is the only line that responds to exogenous GDNF. In contrast, all cell lines respond to GDNF plus GFRα1. Conditioned medium from dorsal root ganglia contains secreted GFRα1 and promotes transformation related phenotypes, which can be blocked by anti-GFRα1 antibody. Perineural invasion in the dorsal root ganglion assay is inhibited by anti-GFRα antibody and RET knockdown. In vivo, knockdown of RET inhibits tumor growth. RET signaling activates ERK or AKT signaling depending on context, but phosphorylation of p70S6 kinase is markedly increased in all cases. Knockdown of p70S6 kinase markedly decreases RET induced transformed phenotypes. Finally, RET is expressed in 18% of adenocarcinomas and all three small cell carcinomas examined. RET promotes transformation associated phenotypes, including perineural invasion in prostate cancer via activation of p70S6 kinase. GFRα1, which is secreted by nerves, is a limiting factor for RET signaling, creating a perineural niche where RET signaling can occur.