CYP27A1 inhibits bladder cancer cells proliferation by regulating cholesterol homeostasis
CYP27A1 inhibits bladder cancer cells proliferation by regulating cholesterol homeostasis
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CYP27A1通过调节胆固醇稳态抑制膀胱癌细胞增殖
DOI：
10.1080/15384101.2018.1558868
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发表时间：
2019-01-02
期刊：
影响因子：
4.3
通讯作者：
Niu, Haitao
中科院分区：
文献类型：
--
作者：
Liang, Zhijuan;Chen, Yuanbin;Niu, Haitao
CYP27A1是一种参与调节细胞胆固醇稳态的酶，可将胆固醇转化为27-羟基胆固醇（27-HC）。研究CYP27A1与细胞增殖的关系，确定CYP27A1在膀胱癌中的作用。采用qRT-PCR和Western blotting检测3种膀胱癌细胞系（T24、UM-UC-3和5637）中CYP27A1的表达，并通过慢病毒感染获得CYP27A1稳定表达的细胞。采用MTT法、集落形成法和肿瘤异种移植模型检测细胞增殖，酶联免疫吸附法（ELISA）检测细胞内27-HC和胆固醇分泌水平。结果显示，与AR阴性的5637细胞相比，雄激素受体（AR）阳性的T24/UM-UC-3细胞中CYP27A1表达下调。在CYP27A1表达恢复后，细胞增殖受到体外和体内的抑制，因为CYP27A1过表达的细胞比对照细胞产生更多的细胞内27-HC。27-HC处理的T24细胞和UM-UC-3细胞结果相似。此外，CYP27A1/27HC可通过肝X受体（LXRs）途径上调atp结合盒转运体G1和A1 (ABCG1和ABCA1)，下调低密度脂蛋白受体（LDLR）表达，从而降低T24和UM-UC-3细胞的细胞胆固醇水平。这些发现都表明CYP27A1在膀胱癌细胞中是一个关键的胆固醇传感器，可能对膀胱癌的增殖有重要作用。
ABSTRACT CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis, converts cholesterol into 27-hydroxycholesterol (27-HC). The relationship between CYP27A1 and cell proliferation was studied to determine the role of CYP27A1 in bladder cancer. The expression of CYP27A1 in three bladder cancer cell lines (T24, UM-UC-3 and 5637) were assessed by qRT-PCR and Western blotting, and cells with stable CYP27A1 expression were generated by lentiviral infection. Cell proliferation was detected by MTT assays, colony formation assays and a tumor xenograft model in vitro and in vivo, and the intracellular 27-HC and cholesterol secretion levels were detected by enzyme-linked immunosorbent assays (ELISA). The results revealed that CYP27A1 expression was downregulated in androgen receptor (AR)-positive T24/UM-UC-3 cells compared with AR-negative 5637 cell. After CYP27A1 expression was restored, cell proliferation was inhibited in vitro and in vivo because much more intracellular 27-HC was produced in the CYP27A1-overexpressing cells than in the control cells. Both T24 and UM-UC-3 cells treated with 27-HC showed similar results. In addition, CYP27A1/27HC could reduce the cellular cholesterol level in both T24 and UM-UC-3 cells by upregulating ATP-binding cassette transporters G1 and A1 (ABCG1 and ABCA1) through Liver X receptors (LXRs) pathway and downregulating low-density lipoprotein receptor (LDLR) expression. These findings all suggest that CYP27A1 is a critical cholesterol sensor in bladder cancer cells that may contribute significantly to bladder cancer proliferation.