KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer
KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer
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DOI：
10.1038/sj.onc.1210036
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发表时间：
2007-04-12
期刊：
影响因子：
8
通讯作者：
Bubendorf, L.
中科院分区：
文献类型：
--
作者：
Bloch, M.;Ousingsawat, J.;Bubendorf, L.
前列腺癌进展的分子机制知之甚少。在这里，我们研究了基因扩增的大电导钙激活钾通道α亚基（KCNMA 1），这是位于染色体区域10 q22。荧光原位杂交（FISH）显示，在119例晚期人类前列腺癌和前列腺癌不敏感细胞系PC-3中，有16%的KCNMA 1扩增。相比之下，KCNMA 1扩增在33例良性对照、32例前驱病变和105例临床器官局限性前列腺癌中不存在。与非扩增对照细胞系相比，扩增与PC-3细胞中的mRNA和蛋白质过表达以及BK通道蛋白和β-雌二醇不敏感的BK电流密度增加相关。用伊比利亚毒素或RNA特异性阻断BK通道（i）可显著抑制PC-3细胞的K+电流和生长。数据表明，10 q22扩增驱动KCNMA 1表达和细胞增殖。因此，KCNMA 1有资格作为前列腺癌患者的一个有前途的诊断和治疗靶点。
Molecular mechanisms of prostate cancer progression are poorly understood. Here, we studied gene amplification of the large conductance calcium-activated potassium channel alpha subunit (KCNMA1), which is located at the chromosomal region 10q22. Fluorescence in situ hybridization ( FISH) revealed KCNMA1 amplification in 16% of 119 late-stage human prostate cancers and in the hormone-insensitive prostate cancer cell line PC-3. In contrast, KCNMA1 amplification was absent in 33 benign controls, 32 precursor lesions and in 105 clinically organ-confined prostate cancers. Amplification was associated with mRNA and protein overexpression as well as increased density of BK channel protein and beta-estradiol-insensitive BK currents in PC-3 cells as compared to non-amplified control cell lines. Specific blockade of BK channels by iberiotoxin or RNA(i) significantly inhibited K+ currents and growth of PC-3 cells. The data demonstrate that 10q22 amplification drives KCNMA1 expression and cell proliferation. Thus, KCNMA1 qualifies as a promising diagnostic and therapeutic target in patients with prostate cancer.