Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility
Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility
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DOI：
10.1158/0008-5472.can-15-0293
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发表时间：
2015-09-01
期刊：
影响因子：
11.2
通讯作者：
Shroyer, Kenneth R.
中科院分区：
文献类型：
--
作者：
Escobar-Hoyos, Luisa F.;Shah, Ruchi;Shroyer, Kenneth R.
在人类癌症中选择性过度表达的角蛋白可能会提供诊断和预后的有用信息。在这项研究中，我们表明，在宫颈癌患者中，在疾病的早期或晚期，角蛋白-17(K17)的高表达预示着不良的预后，在这种情况下，无论是肿瘤分期还是p27缺失(KIP1)，其准确性都超过了p27的阴性预后标志物。我们通过人宫颈、乳腺和胰腺癌细胞的功能丧失和功能获得实验，研究了K17对生物影响的机制基础。具体地说，我们通过调节p27(KIP1)的亚细胞定位和降解来确定K17作为癌蛋白的功能。我们发现K17在细胞周期的G(1)期通过核定位信号(NLS)从中间丝中释放出来并移位到细胞核中，在角蛋白中与p27(KIP1)结合。P27(KIP1)缺乏核输出信号(NES)，需要与CRM1结合的适配器才能进行核输出。在K17中，我们定义并验证了一种富含亮氨酸的NES，它介导了CRM1的结合用于出口。在NLS或NES信号中表达K17突变的宫颈癌细胞表现出核p27(KIP1)水平的增加，而表达野生型K17的细胞表现出总内源性p27(KIP1)的缺失。在宫颈癌的临床标本中，我们证实K17和p27(KIP1)的表达呈负相关，无论是在肿瘤之间还是在单个肿瘤内。总体而言，我们的发现表明，K17作为一种癌蛋白，通过控制p27(KIP1)影响宫颈癌发生的能力，在角蛋白中具有特殊的功能。(C)2015年AACR。
Keratins that are overexpressed selectively in human carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of keratin-17 (K17) predicts poor outcome in patients with cervical cancer, at early or late stages of disease, surpassing in accuracy either tumor staging or loss of p27(KIP1) as a negative prognostic marker in this setting. We investigated the mechanistic basis for the biologic impact of K17 through loss-and gain-of-function experiments in human cervix, breast, and pancreatic cancer cells. Specifically, we determined that K17 functions as an oncoprotein by regulating the subcellular localization and degradation of p27(KIP1). We found that K17 was released from intermediate filaments and translocated into the nucleus via a nuclear localization signal (NLS), specific among keratins, where it bound p27(KIP1) during G(1) phase of the cell cycle. p27(KIP1) lacks a nuclear export signal (NES) and requires an adaptor for CRM1 binding for nuclear export. In K17, we defined and validated a leucine-rich NES that mediated CRM1 binding for export. Cervical cancer cells expressing K17 mutations in its NLS or NES signals exhibited an increase in levels of nuclear p27(KIP1), whereas cells expressing wild-type K17 exhibited a depletion in total endogenous p27(KIP1). In clinical specimens of cervical cancer, we confirmed that the expressions of K17 and p27(KIP1) were inversely correlated, both across tumors and within individual tumors. Overall, our findings establish that K17 functions specially among keratins as an oncoprotein by controlling the ability of p27(KIP1) to influence cervical cancer pathogenesis. (C) 2015 AACR.