Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells
Chronic exposure to cadmium induces a malignant transformation of benign prostate epithelial cells
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DOI：
10.1038/s41389-020-0202-7
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发表时间：
2020-02-17
期刊：
影响因子：
6.2
通讯作者：
Damodaran, Chendil
中科院分区：
文献类型：
--
作者：
Chandrasekaran, Balaji;Dahiya, Nisha R.;Damodaran, Chendil
流行病学证据表明，镉（Cd）是前列腺癌的致病因素之一，但镉对良性前列腺增生（BPH）的影响尚不清楚。本研究的目的是确定镉暴露是否可以恶性转化BPH 1细胞，如果是这样的话，解剖的作用机制。我们通过RNA测序技术对BPH 1转化的分子信号转导机制进行了研究，并确定了镉诱导BPH 1细胞中小脑锌指蛋白2（ZIC 2）的表达。我们注意到，镉暴露增加ZIC 2在镉转化的BPH 1细胞中的表达，这反过来又促进了锚定非依赖性球体和干细胞驱动因子的表达增加，表明它们在干细胞更新中的作用。随后在转化细胞中沉默ZIC 2表达抑制了球体形成、干细胞标志物表达和裸鼠肿瘤生长。在分子水平上，ZIC 2与胶质瘤相关癌基因家族（GLI）锌指1（GLI 1）相互作用，从而激活Cd暴露的BPH 1细胞中的促生存因子（核因子NF κ B、B细胞淋巴瘤-2（Bcl 2）以及X连锁凋亡蛋白抑制剂（XIAP））信号传导。相反，ZIC 2在BPH 1细胞中的过表达导致球状体形成，证实了ZIC 2的致癌功能。在原代BPH细胞中，镉暴露引起的ZIC 2激活和GLI 1信号诱导证实了这种致癌功能的临床意义。最后，人BPH标本与邻近健康组织相比具有增加的ZIC 2。因此，我们报告的直接证据表明，镉暴露诱导良性前列腺增生通过激活ZIC 2和GLI 1信号的恶性转化。
Epidemiological evidence suggests that cadmium (Cd) is one of the causative factors of prostate cancer, but the effect of Cd on benign prostatic hyperplasia (BPH) remains unclear. This study aimed to determine whether Cd exposure could malignantly transform BPH1 cells and, if so, to dissect the mechanism of action. We deciphered the molecular signaling responsible for BPH1 transformation via RNA-sequencing and determined that Cd induced the expression of zinc finger of the cerebellum 2 (ZIC2) in BPH1 cells. We noted Cd exposure increased ZIC2 expression in the Cd-transformed BPH1 cells that in turn promoted anchorage-independent spheroids and increased expression of stem cell drivers, indicating their role in stem cell renewal. Subsequent silencing of ZIC2 expression in transformed cells inhibited spheroid formation, stem cell marker expression, and tumor growth in nude mice. At the molecular level, ZIC2 interacts with the glioma-associated oncogene family (GLI) zinc finger 1 (GLI1), which activates prosurvival factors (nuclear factor NF kappa B, B-cell lymphoma-2 (Bcl2), as well as an X-linked inhibitor of apoptosis protein (XIAP)) signaling in Cd-exposed BPH1 cells. Conversely, overexpression of ZIC2 in BPH1 cells caused spheroid formation confirming the oncogenic function of ZIC2. ZIC2 activation and GLI1 signaling induction by Cd exposure in primary BPH cells confirmed the clinical significance of this oncogenic function. Finally, human BPH specimens had increased ZIC2 versus adjacent healthy tissues. Thus, we report direct evidence that Cd exposure induces malignant transformation of BPH via activation of ZIC2 and GLI1 signaling.