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首页> 外文期刊>Molecular Cancer >Id4 deficiency attenuates prostate development and promotes PIN-like lesions by regulating androgen receptor activity and expression of NKX3.1 and PTEN
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Id4 deficiency attenuates prostate development and promotes PIN-like lesions by regulating androgen receptor activity and expression of NKX3.1 and PTEN

机译：Id4缺乏症通过调节雄激素受体活性以及NKX3.1和PTEN的表达来减弱前列腺发育并促进PIN样病变

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Background Inhibitor of differentiation 4 (Id4), a member of the helix-loop-helix family of transcriptional regulators has emerged as a tumor suppressor in prostate cancer. Id4 is expressed in the normal prostate where its expression is also regulated by androgens. In this study we investigated the effect of loss of Id4 (Id4-/-) on adult prostate morphology. Methods Histological analysis was performed on prostates from 6-8 weeks old Id4-/-, Id4+/- and Id4+/+ mice. Expression of Id1, Sox9, Myc, androgen receptor, Akt, p-Akt, Pten and Nkx3.1 was investigated by immunohistochemistry. Androgen receptor binding on NKX3.1 promoter was studied by chromatin immuno-precipitation. Id4 was either over-expressed or silenced in prostate cancer cell lines DU145 and LNCaP respectively followed by analysis of PTEN , NKX3.1 and Sox9 expression. Results Id4-/- mice had smaller prostates with fewer tubules, smaller tubule diameters and subtle mPIN like lesions. Levels of androgen receptor were similar between wild type and Id4-/- prostate. Decreased NKX3.1 expression was in part due to decreased androgen receptor binding on NKX3.1 promoter in Id4-/- mice. The increase in the expression of Myc, Sox9, Id1, Ki67 and decrease in the expression of PTEN , Akt and phospho-AKT was associated with subtle mPIN like lesions in Id4-/- prostates. Finally, prostate cancer cell line models in which Id4 was either silenced or over-expressed confirmed that Id4 regulates NKX3.1, Sox9 and PTEN . Conclusions Our results suggest that loss of Id4 attenuates normal prostate development and promotes hyperplasia/dysplasia with subtle mPIN like lesions characterized by gain of Myc and Id1 and loss of Nkx3.1 and Pten expression. One of the mechanisms by which Id4 may regulate normal prostate development is through regulating androgen receptor binding to respective response elements such as those on NKX3.1 promoter. In spite of these complex alterations, large neoplastic lesions in Id4-/- prostates were not observed suggesting the possibility of mechanisms/pathways such as loss of Akt that could restrain the formation of significant pre-cancerous lesions.
机译：背景分化分化抑制剂4（Id4）是转录调节剂的螺旋-环-螺旋家族的成员，已经成为前列腺癌中的肿瘤抑制剂。 Id4在正常前列腺中表达，其表达也受雄激素调节。在这项研究中，我们调查了Id4（Id4-/-）丢失对成人前列腺形态的影响。方法对6-8周龄Id4-/-，Id4 +/-和Id4 + / +小鼠的前列腺进行组织学分析。通过免疫组织化学研究了Id1，Sox9，Myc和雄激素受体，Akt，p-Akt，Pten和Nkx3.1的表达。通过染色质免疫沉淀研究雄激素受体在NKX3.1启动子上的结合。分别在前列腺癌细胞系DU145和LNCaP中过表达或沉默Id4，然后分析PTEN，NKX3.1和Sox9表达。结果Id4-/-小鼠的前列腺较小，肾小管较少，肾小管直径较小，并有细微的mPIN样病变。野生型和Id4-/-前列腺之间的雄激素受体水平相似。 NKX3.1表达降低部分是由于Id4-/-小鼠中雄激素受体在NKX3.1启动子上的结合减少。 Myc，Sox9，Id1，Ki67表达的增加以及PTEN，Akt和磷酸化AKT表达的减少与Id4-/-前列腺中微妙的mPIN样病变有关。最后，其中Id4沉默或过表达的前列腺癌细胞模型证实了Id4调节NKX3.1，Sox9和PTEN。结论我们的结果表明，Id4的丧失会减弱正常的前列腺发育并促进增生/增生，并伴有以Myc和Id1的获得以及Nkx3.1和Pten表达的丧失为特征的细微mPIN样病变。 Id4调节正常前列腺发育的机制之一是通过调节雄激素受体与相应反应元件（例如NKX3.1启动子上的那些反应元件）的结合。尽管存在这些复杂的变化，但未观察到Id4-/-前列腺中的大的肿瘤性病变，提示可能会抑制重要的癌前病变形成的机制/途径（如Akt丢失）。

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