Conditional gene regulation models demonstrate a pro-proliferative role for growth hormone receptor in prostate cancer.
Conditional gene regulation models demonstrate a pro-proliferative role for growth hormone receptor in prostate cancer.
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条件基因调控模型证明生长激素受体在前列腺癌中具有促增殖作用。
DOI：
10.1002/pros.24474
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Marker,PaulC
中科院分区：
文献类型：
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作者：
Unterberger,ChristopherJ;McIlwain,SeanJ;Tsourkas,PhilipposK;Maklakova,VilenaI;Prince,JordynL;Onesti,Abigail;Hu,Rong;Kopchick,JohnJ;Swanson,StevenM;Marker,PaulC
研究背景：生长激素受体（GHR）失活突变的人患癌症（包括前列腺癌）的几率较低。同样，在C3（1）/TAg前列腺癌模型中，Ghr失活突变的小鼠也不会发生前列腺上皮内瘤变。然而，这些模型在临床相关性方面仍然存在差距。目前的研究解决了这些差距和正在进行的作用ofGhrin前列腺癌使用的功能丧失和增益的functionmodels. MethodsConditionalGhrin激活在C3（1）/TAg模型中实现采用他莫昔芬诱导的Cre和前列腺特异性Cre。同时，还使用转基因GH拮抗剂。评估了6个月龄小鼠前列腺的病理学、增殖和基因表达。对癌症基因组图谱数据进行分析，以确定人类前列腺癌亚组中的GH过表达。使用稳定的转染子在PTEN-P2和TRAMP-C2小鼠前列腺癌细胞中对GH过表达进行建模。生长，增殖和基因表达的影响ofGhroverexpression进行了评估，在体外和invivo.ResultsLoss-of-function forGhr全球或前列腺上皮细胞减少增殖和分层的前列腺上皮细胞在C3（1）/TAg模型。例如，参与免疫系统和肿瘤发生的基因和基因组在globalGhr破坏后失调。癌症基因组图谱的分析显示，具有ERG融合基因或ETV 1融合基因的人前列腺癌中GHR表达较高。在这些人前列腺癌中观察到的GHR过表达模型通过过表达Ghrin小鼠前列腺癌细胞与多克隆Ptenor T抗原驱动基因增加了前列腺癌细胞的体外和体内增殖。GHR过表达调节多个基因的表达，与GHR功能丧失模型相反。这些数据表明，人前列腺上皮细胞中GHR活性的变化在前列腺癌的增殖和基因调控中起作用，表明例如通过FDA批准的GH拮抗剂pegvisomant破坏GH信号传导的潜力可能有益于治疗前列腺癌。
BackgroundHumans with inactivating mutations in growth hormone receptor (GHR) have lower rates of cancer, including prostate cancer. Similarly, mice with inactivatingGhrmutations are protected from prostatic intraepithelial neoplasia in the C3(1)/TAg prostate cancer model. However, gaps in clinical relevance in those models persist. The current study addresses these gaps and the ongoing role ofGhrin prostate cancer using loss‐of‐function and gain‐of‐function models.MethodsConditionalGhrinactivation was achieved in the C3(1)/TAg model by employing a tamoxifen‐inducible Cre and a prostate‐specific Cre. In parallel, a transgenic GH antagonist was also used. Pathology, proliferation, and gene expression of 6‐month old mouse prostates were assessed. Analysis of The Cancer Genome Atlas data was conducted to identifyGHRoverexpression in a subset of human prostate cancers.Ghroverexpression was modeled in PTEN‐P2 and TRAMP‐C2 mouse prostate cancer cells using stable transfectants. The growth, proliferation, and gene expression effects ofGhroverexpression was assessed in vitro and in vivo.ResultsLoss‐of‐function forGhrglobally or in prostatic epithelial cells reduced proliferation and stratification of the prostatic epithelium in the C3(1)/TAg model. Genes and gene sets involved in the immune system and tumorigenesis, for example, were dysregulated upon globalGhrdisruption. Analysis of The Cancer Genome Atlas revealed higherGHRexpression in human prostate cancers with ERG‐fusion genes or ETV1‐fusion genes. Modeling theGHRoverexpression observed in these human prostate cancers by overexpressingGhrin mouse prostate cancer cells with mutantPtenor T‐antigen driver genes increased proliferation of prostate cancer cells in vitro and in vivo.Ghroverexpression regulated the expression of multiple genes oppositely toGhrloss‐of‐function models.ConclusionsLoss‐of‐function and gain‐of‐functionGhrmodels, including prostatic epithelial cell specific alterations inGhr, altered proliferation, and gene expression. These data suggest that changes in GHR activity in human prostatic epithelial cells play a role in proliferation and gene regulation in prostate cancer, suggesting the potential for disrupting GH signaling, for example by the FDA approved GH antagonist pegvisomant, may be beneficial in treating prostate cancer.