MicroRNA-185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the SREBP metabolic pathway in prostate cancer cells.
MicroRNA-185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the SREBP metabolic pathway in prostate cancer cells.
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DOI：
10.1371/journal.pone.0070987
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Huang WC
中科院分区：
文献类型：
--
作者：
Li X;Chen YT;Josson S;Mukhopadhyay NK;Kim J;Freeman MR;Huang WC
microRNA（miRNA或miR）抑制致癌相关通路已被证明是一种有前途的癌症治疗方法。异常的脂质和胆固醇代谢参与前列腺癌的发展和进展到终末期疾病。我们最近发现，脂肪生成的关键转录因子，固醇调节元件结合蛋白-1（SREBP-1），诱导脂肪酸和脂质的积累和雄激素受体（AR）的转录活性，也促进前列腺癌细胞的生长和去势抵抗。SREBP-1在人前列腺癌和去势抵抗患者标本中过表达。这些实验和临床结果表明，SREBP-1是一个潜在的致癌转录因子在前列腺癌。在这项研究中，我们确定了两种miRNA，miR-185和342，通过抑制SREBP-1和2的表达并下调其靶基因，包括脂肪酸合成酶（FXR）和3-羟基-3-甲基戊二酰CoA还原酶（HMGCR），控制前列腺癌细胞中的脂肪生成和胆固醇生成。miR-185和342均抑制前列腺癌细胞培养物和异种移植物模型中的致瘤性、细胞生长、迁移和侵袭，这与它们对脂肪生成和胆固醇生成的阻断一致。与非癌性上皮细胞相比，前列腺癌细胞中内源性miR-185和342表达显著降低。miR-185和342的恢复导致前列腺癌细胞中caspase依赖性凋亡死亡。新发现的miRNAs，miR-185和342，代表了前列腺癌治疗的新靶向机制。
MicroRNA (miRNA or miR) inhibition of oncogenic related pathways has been shown to be a promising therapeutic approach for cancer. Aberrant lipid and cholesterol metabolism is involved in prostate cancer development and progression to end-stage disease. We recently demonstrated that a key transcription factor for lipogenesis, sterol regulatory element-binding protein-1 (SREBP-1), induced fatty acid and lipid accumulation and androgen receptor (AR) transcriptional activity, and also promoted prostate cancer cell growth and castration resistance. SREBP-1 was overexpressed in human prostate cancer and castration-resistant patient specimens. These experimental and clinical results indicate that SREBP-1 is a potential oncogenic transcription factor in prostate cancer. In this study, we identified two miRNAs, miR-185 and 342, that control lipogenesis and cholesterogenesis in prostate cancer cells by inhibiting SREBP-1 and 2 expression and down-regulating their targeted genes, including fatty acid synthase (FASN) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR). Both miR-185 and 342 inhibited tumorigenicity, cell growth, migration and invasion in prostate cancer cell culture and xenograft models coincident with their blockade of lipogenesis and cholesterogenesis. Intrinsic miR-185 and 342 expression was significantly decreased in prostate cancer cells compared to non-cancerous epithelial cells. Restoration of miR-185 and 342 led to caspase-dependent apoptotic death in prostate cancer cells. The newly identified miRNAs, miR-185 and 342, represent a novel targeting mechanism for prostate cancer therapy.
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