Roles for the stem cell-associated intermediate filament nestin in prostate cancer migration and metastasis
Roles for the stem cell-associated intermediate filament nestin in prostate cancer migration and metastasis
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DOI：
10.1158/0008-5472.can-07-0806
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Berman, David M.
中科院分区：
文献类型：
--
作者：
Kleeberger, Wolfram;Bova, G. Steven;Berman, David M.
中间丝蛋白Nestin鉴定成体组织中的干/祖细胞，但Nestin的功能知之甚少。我们研究了巢蛋白在常见致命性癌症中的表达和功能。巢蛋白mRNA在来自小细胞肺癌和乳腺癌的细胞系中被检测到，并且特别是在来自前列腺癌转移的细胞系中升高。而雄激素非依赖性系PC 3，22 RVI，和DU 145在标准培养条件下表达巢蛋白转录，雄激素依赖性系LnCaP表达巢蛋白只有雄激素撤退。我们通过对254例前列腺癌患者样本的免疫组织化学分析，证实了巢蛋白表达、雄激素戒断和转移潜能的相关性。细胞质巢蛋白在75%的雄激素非依赖性致死性疾病患者的前列腺癌细胞中很容易识别，即使在前列腺本身的癌症样本中也是如此。然而，巢蛋白的表达是检测不到的局部雄激素剥夺肿瘤和转移，而事先雄激素剥夺。为了解决其功能，我们用短发夹RNA降低巢蛋白水平，显著抑制前列腺癌细胞的体外迁移和侵袭，但保持细胞生长完整。巢蛋白敲除也减少转移5倍，与对照相比，尽管在接种部位的致瘤性不受影响。这些结果说明巢蛋白在细胞运动中的功能，并确定了前列腺癌转移的新途径。该通路的活性可能是由前列腺外环境选择的，或者如我们的数据所支持的，可能起源于雄激素剥夺后的前列腺内。进一步解剖这种新的巢蛋白迁移途径可能会导致战略，以防止和中和转移扩散。
The intermediate filament protein Nestin identifies stem/ progenitor cells in adult tissues, but the function of Nestin is poorly understood. We investigated Nestin expression and function in common lethal cancers. Nestin mRNA was detected in cell lines from small cell lung, and breast cancers, and particularly elevated in cell lines derived from prostate cancer metastases. Whereas the androgen-independent lines PC3, 22RVI, and DU145 all expressed Nestin transcripts under standard culture conditions, the androgen-dependent line LnCaP expressed Nestin only on androgen withdrawal. We confirmed associations of Nestin expression, androgen withdrawal, and metastatic potential by inummohistochemical analysis of samples from 254 prostate cancer patients. Cytoplasmic Nestin protein was readily identifiable in prostate cancer cells from 75% of patients with lethal androgen-independent disease, even in cancer sampled from the prostate itself. However, Nestin expression was undetectable in localized androgen-deprived tumors and in metastases without prior androgen deprivation. To address its function, we reduced Nestin levels with short hairpin RNAs, markedly inhibiting in vitro migration and invasion in prostate cancer cells but leaving cell growth intact. Nestin knockdown also diminished metastases 5-fold compared with controls despite uncompromised tumorigenicity at the site of inoculation. These results specify a function for Nestin in cell motility and identify a novel pathway for prostate cancer metastasis. Activity of this pathway may be selected by the extraprostatic environment or, as supported by our data, may originate within the prostate after androgen deprivation. Further dissection of this novel Nestin migration pathway may lead to strategies to prevent and neutralize metastatic spread.