Nuclear versus cytoplasmic localization of filamin A in prostate cancer: immunohistochemical correlation with metastases.
Nuclear versus cytoplasmic localization of filamin A in prostate cancer: immunohistochemical correlation with metastases.
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DOI：
10.1158/1078-0432.ccr-08-1402
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发表时间：
2009-02-01
期刊：
影响因子：
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通讯作者：
Ghosh PM
中科院分区：
文献类型：
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作者：
Bedolla RG;Wang Y;Asuncion A;Chamie K;Siddiqui S;Mudryj MM;Prihoda TJ;Siddiqui J;Chinnaiyan AM;Mehra R;de Vere White RW;Ghosh PM
我们先前表明肌动蛋白结合蛋白FilaminA（FlnA）的核定位对应于前列腺癌中的细胞毒性依赖性（Oncogene，2007，26：6061-6070）。完整的FlnA（280 kDa，胞质）切割成90 kDa的片段，在未处理细胞中易位到细胞核中，而在处理难治性细胞中，FlnA被磷酸化，阻止其切割和核易位。我们现在研究FlnA定位是否决定了晚期雄激素非依赖性前列腺癌的转移倾向。我们研究，通过免疫组织化学，FlnA定位在石蜡包埋的人前列腺组织代表不同阶段的进展。结果与前列腺癌细胞模型的体外研究相关。与转移性前列腺癌（0.3719±0.4992，p=0.0007）相比，良性前列腺（0.6612±0.5888）、PIN（0.6024±0.4620）和临床局限性癌症（0.69134±0.5686）中的核FlnA显著更高。胞浆FlnA从良性前列腺（0.0833±0.2677）、PIN（0.1409±0.2293）、局限性癌（0.3008±0.3762，p=0.0150）到转移癌（0.7632±0.4414，p<0.00001）增加。转移性与非转移性组织的Logistic回归得到ROC曲线下面积，核-FlnA为0.67，胞质-FlnA为0.79，两者均为0.82，表明转移与胞质-核易位相关。体外研究表明，FlnA的胞浆定位诱导细胞侵袭，而蛋白质的核转位抑制它。FlnA去磷酸化与PKA抑制剂H-89促进FlnA核转位，导致侵袭力和AR转录活性降低，并诱导雄激素戒断的敏感性在卵巢癌难治性细胞。本研究中的数据表明，在前列腺癌中，转移与FlnA的细胞质定位相关，并且可以通过该蛋白的裂解和随后的核转位来预防。
We previously showed that nuclear localization of the actin-binding protein FilaminA (FlnA) corresponded to hormone-dependence in prostate cancer (Oncogene, 2007, 26:6061-6070). Intact FlnA (280kDa, cytoplasmic) cleaved to a 90kDa fragment which translocated to the nucleus in hormone-naïve cells, whereas in hormone-refractory cells, FlnA was phosphorylated, preventing its cleavage and nuclear translocation. We now examined whether FlnA localization determines a propensity to metastasis in advanced androgen independent prostate cancer. We examined, by immunohistochemistry, FlnA localization in paraffin-embedded human prostate tissue representing different stages of progression. Results were correlated with in vitro studies in a cell model of prostate cancer. Nuclear FlnA was significantly higher in benign prostate (0.6612±0.5888), PIN (0.6024±0.4620) and clinically localized cancers (0.69134±0.5686), compared to metastatic prostate cancers (0.3719±0.4992, p=0.0007). Cytoplasmic FlnA increased from benign prostate (0.0833±0.2677), PIN (0.1409±0.2293), localized cancers (0.3008±0.3762, p=0.0150), to metastases (0.7632±0.4414, p<0.00001). Logistic regression of metastatic vs non-metastatic tissue yielded the area-under-ROC curve as 0.67 for nuclear-FlnA, 0.79 for cytoplasmic-FlnA and 0.82 for both, indicating that metastasis correlates with cytoplasmic-to-nuclear translocation. In vitro studies showed that cytoplasmic localization of FlnA induced cell invasion whereas nuclear translocation of the protein inhibited it. FlnA dephosphorylation with the PKA inhibitor H-89 facilitated FlnA nuclear translocation, resulting in decreased invasiveness and AR transcriptional activity, and induced sensitivity to androgen withdrawal in hormone-refractory cells. The data presented in this study indicate that in prostate cancer, metastasis correlates with cytoplasmic localization of FlnA and may be prevented by cleavage and subsequent nuclear translocation of this protein.