The role of microRNA-221 and microRNA-222 in androgen-independent prostate cancer cell lines.
The role of microRNA-221 and microRNA-222 in androgen-independent prostate cancer cell lines.
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DOI：
10.1158/0008-5472.can-08-4112
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发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Kantoff P
中科院分区：
文献类型：
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作者：
Sun T;Wang Q;Balk S;Brown M;Lee GS;Kantoff P
雄激素依赖性前列腺癌在雄激素剥夺治疗后通常进展为去势抵抗性前列腺癌（CRPC）。microRNAs（miRs）是一类非编码小分子RNA（19- 25 nt），在基因表达调控中起重要作用。最近的研究表明，miR的表达模式在正常和肿瘤性前列腺上皮细胞中有显着差异。然而，miR在CRPC发展中的重要性尚未得到探索。通过进行miR的全基因组表达谱分析，我们发现与雄激素依赖性前列腺癌细胞系（LNCaP）中的miR-221和miR-222的表达水平相比，CRPC细胞（LNCaP衍生的细胞系LNCaP-Abl）中的miR-221和miR-222的表达水平显著增加。miR-221或-222在LNCaP或另一种AD细胞系LAPC-4中的过表达显著降低了双氢睾酮（DHT）诱导的PSA表达上调的水平，并增加了LNCaP细胞的雄激素非依赖性生长。在LNCaP-Abl细胞系中用拮抗剂miR敲低miR-221和-222的表达水平恢复了对DHT诱导PSA转录的响应，并且还增加了LNCaP-Abl细胞对雄激素处理的生长响应。在LNCaP细胞中，单独改变p27/kip 1（miR-221和-222的已知靶点）的表达水平会影响DHT非依赖性细胞生长，但不会显著影响PSA转录对DHT处理的响应。总之，我们的数据表明miR-221和-222参与CRPC表型的发展或维持。
Androgen-dependent prostate cancer typically progresses to castration resistant prostate cancer (CRPC) after the androgen deprivation therapy. MicroRNAs (miRs) are non-coding small RNAs (19-25nt) that play an important role in the regulation of gene expression. Recent studies have shown that miR expression patterns are significantly different in normal and neoplastic prostate epithelial cells. However, the importance of miRs in the development of CRPC has not yet been explored. By performing genome-wide expression profiling of miRs, we found that expression levels of several miRs, in particular miR-221 and miR-222, were significantly increased in CRPC cells (the LNCaP derived cell line LNCaP-Abl), compared with those in the Androgen-dependent prostate cancer cell line (LNCaP). Over-expression of miR-221 or -222 in LNCaP or another AD cell line, LAPC-4 significantly reduced the level of the dihydrotestosterone (DHT) induced up-regulation of PSA expression and increased androgen independent growth of LNCaP cells. Knocking down the expression level of miR-221 and -222 with antagonist miRs in the LNCaP-Abl cell line restored the response to the DHT induction of PSA transcription and also increased the growth response of the LNCaP-Abl cells to the androgen treatment. Changing the expression level of p27/kip1, a known target of miR-221 and -222, alone, in LNCaP cells affected the DHT independent cell growth, but did not significantly influence the response of PSA transcription to the DHT treatment. In conclusion, our data suggest the involvement of miR-221 and -222 in the development or maintenance of the CRPC phenotype.