Dual Action of miR-125b As a Tumor Suppressor and OncomiR-22 Promotes Prostate Cancer Tumorigenesis.
Dual Action of miR-125b As a Tumor Suppressor and OncomiR-22 Promotes Prostate Cancer Tumorigenesis.
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DOI：
10.1371/journal.pone.0142373
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zehner ZE
中科院分区：
文献类型：
--
作者：
Budd WT;Seashols-Williams SJ;Clark GC;Weaver D;Calvert V;Petricoin E;Dragoescu EA;O'Hanlon K;Zehner ZE
MicroRNAs （miRs）是一类新型的小RNA分子，其失调可导致癌症。一种组合方法被用来鉴定在一组独特的前列腺癌细胞系中促进前列腺癌进展的mir，这些前列腺癌细胞系起源于亲本p69细胞系，并延伸到高度致瘤性/转移性M12亚系。总之，这些细胞系被认为在体内模拟前列腺癌的进展。先前的网络分析和miR阵列表明，hsa-miR-125b的缺失和hsa-miR-22的过表达可能有助于前列腺肿瘤的发生。与通过激光捕获显微解剖从根治性前列腺切除术中收集的邻近良性腺上皮相比，在人类前列腺肿瘤样本中证实了这两个miRs的失调。事实上，hsa-miR-125b表达的改变似乎是肿瘤发生的早期事件。逆相微阵列蛋白质组学分析显示，与亲本p69细胞相比，M12肿瘤细胞中的ErbB2/3、PI3K/AKT和MAPK/ERK通路下游成员以及PTEN是差异表达的蛋白靶点。相关的荧光素酶+3′-UTR表达研究证实了hsa-miR-125b与ErbB2以及hsa-miR-22与PTEN之间的直接相互作用。恢复hsa-miR-125b或通过拮抗剂抑制hsa-miR-22的表达可在体外改变M12肿瘤细胞的行为。因此，hsa-miR-125b作为肿瘤抑制因子和hsa-miR-22作为肿瘤抑制因子的双重作用通过调节PI3K/AKT和MAPK/ERK信号通路（已知影响前列腺癌进展的关键途径）促进了前列腺肿瘤的发生。
MicroRNAs (miRs) are a novel class of small RNA molecules, the dysregulation of which can contribute to cancer. A combinatorial approach was used to identify miRs that promote prostate cancer progression in a unique set of prostate cancer cell lines, which originate from the parental p69 cell line and extend to a highly tumorigenic/metastatic M12 subline. Together, these cell lines are thought to mimic prostate cancer progression in vivo. Previous network analysis and miR arrays suggested that the loss of hsa-miR-125b together with the overexpression of hsa-miR-22 could contribute to prostate tumorigenesis. The dysregulation of these two miRs was confirmed in human prostate tumor samples as compared to adjacent benign glandular epithelium collected through laser capture microdissection from radical prostatectomies. In fact, alterations in hsa-miR-125b expression appeared to be an early event in tumorigenesis. Reverse phase microarray proteomic analysis revealed ErbB2/3 and downstream members of the PI3K/AKT and MAPK/ERK pathways as well as PTEN to be protein targets differentially expressed in the M12 tumor cell compared to its parental p69 cell. Relevant luciferase+3’-UTR expression studies confirmed a direct interaction between hsa-miR-125b and ErbB2 and between hsa-miR-22 and PTEN. Restoration of hsa-miR-125b or inhibition of hsa-miR-22 expression via an antagomiR resulted in an alteration of M12 tumor cell behavior in vitro. Thus, the dual action of hsa-miR-125b as a tumor suppressor and hsa-miR-22 as an oncomiR contributed to prostate tumorigenesis by modulations in PI3K/AKT and MAPK/ERK signaling pathways, key pathways known to influence prostate cancer progression.