Hewa Bostanthirige Dhanushka, Komaragiri Shravan K, Joshi Jugal B, Alzahrani Majid, Saini Isha, Jain Sanjay, Bowen Nathan J, Havrda Matthew C, Chaudhary Jaideep
Center for Cancer Research and Therapeutics Development, Clark Atlanta University, Atlanta GA, USA.
Lifeline Pathology Lab and Diagnostic Center, Karnal, India.
Oncoscience. 2021 Mar 24;8:14-30. doi: 10.18632/oncoscience.524. eCollection 2021.
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. In this study we investigated the effect of loss of Id4 () on mouse prostate development. Histological analysis was performed on prostates from 25 days, 3 months and 6 months old mice. Expression of Amacr, Ck8, Ck18, Fkbp51, Fkbp52, androgen receptor, Pten, sca-1 and Nkx3.1 was investigated by immunohistochemistry. Results were compared to the prostates from mice. mice had smaller prostates with fewer and smaller tubules. Subtle PIN like lesions were observed at 6mo. Decreased Nkx3.1 and Pten and increased stem cell marker sca-1, PIN marker Amacr and basal cell marker p63 was observed at all ages. Persistent Ck8 and Ck18 expression suggested that loss of Id4 results in epithelial commitment but not terminal differentiation in spite of active Ar. Loss of Id4 attenuates normal prostate development and promotes hyperplasia/ dysplasia with PIN like lesions. The results suggest that loss of Id4 maintains stem cell phenotype of "luminal committed basal cells", identifying a unique prostate developmental pathway regulated by Id4.
分化抑制因子4（Id4）是转录调节因子螺旋-环-螺旋家族的成员，已成为前列腺癌中的一种肿瘤抑制因子。在本研究中，我们调查了Id4缺失对小鼠前列腺发育的影响。对25天、3个月和6个月大的小鼠前列腺进行了组织学分析。通过免疫组织化学研究了Amacr、Ck8、Ck18、Fkbp51、Fkbp52、雄激素受体、Pten、sca-1和Nkx3.1的表达。将结果与野生型小鼠的前列腺进行比较。Id4缺失的小鼠前列腺较小，小管数量减少且管径变小。在6个月时观察到轻微的PIN样病变。在所有年龄段均观察到Nkx3.1和Pten减少，干细胞标志物sca-1、PIN标志物Amacr和基底细胞标志物p63增加。持续的Ck8和Ck18表达表明，尽管雄激素受体（Ar）活跃，但Id4缺失导致上皮定向分化而非终末分化。Id4缺失会减弱正常前列腺发育，并促进伴有PIN样病变的增生/发育异常。结果表明，Id4缺失维持了“管腔定向基底细胞”的干细胞表型，确定了一条由Id4调节的独特前列腺发育途径。
