MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A.
MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A.
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激素敏感性前列腺癌通常在雄激素剥夺治疗后进展为去势抵抗性前列腺癌（CRPC）。我们研究了 microRNA (miR) 在前列腺癌向 CRPC 转变中的影响。 MiR-221/-222 在骨转移性 CRPC 肿瘤标本中高表达。我们之前证明，LNCaP 中 miR-221/-222 的瞬时过表达促进了 CRPC 表型的发展。在当前的研究中，我们表明，稳定过表达 miR-221 通过挽救 LNCaP 细胞免受由于缺乏雄激素而导致的 G1 期生长停滞，从而赋予 LNCaP 雄激素非依赖性 (AI) 细胞生长。 LNCaP 中 miR-221 的过表达减少了雄激素反应基因亚组的转录，而不影响雄激素受体 (AR) 或 AR 雄激素完整性。通过进行系统的生化和生物信息分析，我们确定了两个 miR-221 靶标 HECTD2 和 RAB1A，它们可以介导多种前列腺癌细胞系中 CRPC 表型的发展。 HECTD2 的下调显着影响雄激素诱导和 AR 介导的转录，HECTD2 或 RAB1A 的下调可增强 AI 细胞的生长。由于 miR-221 表达升高，许多细胞周期基因的表达发生改变，促进上皮间质转化/肿瘤转移的途径被激活。我们假设 miR-221 上调的一个主要生物学后果是 AR 信号的重编程，这反过来可能介导向 CRPC 表型的转变。
Hormone-sensitive prostate cancer typically progresses to castration resistant prostate cancer (CRPC) after the androgen deprivation therapy. We investigated the impact of microRNAs (miRs) in the transition of prostate cancer to CRPC. MiR-221/-222 was highly expressed in bone metastatic CRPC tumor specimens. We previously demonstrated that transient overexpression of miR-221/-222 in LNCaP promoted the development of the CRPC phenotype. In current study, we show that stably overexpressing miR-221 confers androgen independent (AI) cell growth in LNCaP by rescuing LNCaP cells from growth arrest at G1 phase due to the lack of androgen. Overexpressing of miR-221 in LNCaP reduced the transcription of a subgroup of androgen-responsive genes without affecting the androgen receptor (AR) or AR-androgen integrity. By performing systematic biochemical and bioinformatical analyses, we identified two miR-221 targets, HECTD2 and RAB1A, which could mediate the development of CRPC phenotype in multiple prostate cancer cell lines. Downregulation of HECTD2 significantly affected the androgen-induced and AR-mediated transcription, and downregulation of HECTD2 or RAB1A enhances AI cell growth. As a result of the elevated expression of miR-221, expression of many cell cycle genes was altered and pathways promoting epithelial to mesenchymal transition/tumor metastasis were activated. We hypothesize that a major biological consequence of upregulation of miR-221 is reprogramming of AR signaling, which in turn may mediate the transition to the CRPC phenotype.
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影响因子：
3.7
作者：
Love HD;Booton SE;Boone BE;Breyer JP;Koyama T;Revelo MP;Shappell SB;Smith JR;Hayward SW
通讯作者：
Hayward SW
影响因子：
4.3
作者：
Rini, Brian I;Small, Eric J
通讯作者：
Small, Eric J
影响因子：
4.8
作者：
Miller, Tyler E.;Ghoshal, Kalpana;Majumder, Sarmila
通讯作者：
Majumder, Sarmila
影响因子：
11.4
作者：
Chen, Zhong;Zhang, Chunpeng;Wang, Qianben
通讯作者：
Wang, Qianben
影响因子：
50.3
作者：
Garofalo M;Di Leva G;Romano G;Nuovo G;Suh SS;Ngankeu A;Taccioli C;Pichiorri F;Alder H;Secchiero P;Gasparini P;Gonelli A;Costinean S;Acunzo M;Condorelli G;Croce CM
通讯作者：
Croce CM