Loss of keratin 8 phosphorylation leads to increased tumor progression and correlates with clinico-pathological parameters of OSCC patients.
Loss of keratin 8 phosphorylation leads to increased tumor progression and correlates with clinico-pathological parameters of OSCC patients.
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角蛋白8磷酸化的丧失导致肿瘤进展增加，并与OSCC患者的临床病理参数相关。
DOI：
10.1371/journal.pone.0027767
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Vaidya MM
中科院分区：
文献类型：
--
作者：
Alam H;Gangadaran P;Bhate AV;Chaukar DA;Sawant SS;Tiwari R;Bobade J;Kannan S;D'cruz AK;Kane S;Vaidya MM
角蛋白是细胞质中具有组织特异性和分化依赖性的中间丝蛋白。角蛋白8和18 （K8和K18）主要在简单上皮组织中表达，并具有机械和调节功能。K8和K18的异常表达与人类口腔鳞状细胞癌（OSCCs）的肿瘤进展、侵袭和不良预后有关。K8和K18经历了包括磷酸化在内的多种翻译后修饰，这些修饰在各种细胞过程中调节它们的功能。虽然已知K8和K18磷酸化调节细胞周期、细胞生长和凋亡，但其在细胞迁移和/或肿瘤进展中的意义在很大程度上尚不清楚。在本研究中，我们研究了K8磷酸化在OSCC细胞迁移和/或肿瘤进展中的作用。为了了解K8磷酸化在OSCC肿瘤进展中的作用，在K8敲除的人AW13516细胞（来源于舌SCC，先前生成）中，Ser73和Ser431的shrna耐药K8磷酸化突变体过表达。在NOD-SCID小鼠的伤口愈合实验和肿瘤生长实验中，分别分析过表达克隆的细胞运动性和致瘤性。与K8野生型克隆相比，过表达的K8磷酸化突变体克隆的细胞迁移和致瘤性显著增加。此外，通过免疫组织化学分析，在人OSCC组织中也观察到K8 Ser73和Ser431磷酸化的缺失，它们的去磷酸化与肿瘤的大小、淋巴结转移和分期显著相关。我们的研究结果首次证明了K8磷酸化在OSCC细胞迁移和/或致瘤性中的潜在作用。此外，K8去磷酸化与OSCC患者临床病理参数的相关性研究也提示其可能用于人类OSCC的预后。
Keratins are cytoplasmic intermediate filament proteins expressed in tissue specific and differentiation dependent manner. Keratins 8 and 18 (K8 and K18) are predominantly expressed in simple epithelial tissues and perform both mechanical and regulatory functions. Aberrant expression of K8 and K18 is associated with neoplastic progression, invasion and poor prognosis in human oral squamous cell carcinomas (OSCCs). K8 and K18 undergo several post-translational modifications including phosphorylation, which are known to regulate their functions in various cellular processes. Although, K8 and K18 phosphorylation is known to regulate cell cycle, cell growth and apoptosis, its significance in cell migration and/or neoplastic progression is largely unknown. In the present study we have investigated the role of K8 phosphorylation in cell migration and/or neoplastic progression in OSCC. To understand the role of K8 phosphorylation in neoplastic progression of OSCC, shRNA-resistant K8 phospho-mutants of Ser73 and Ser431 were overexpressed in K8-knockdown human AW13516 cells (derived from SCC of tongue; generated previously). Wound healing assays and tumor growth in NOD-SCID mice were performed to analyze the cell motility and tumorigenicity respectively in overexpressed clones. The overexpressed K8 phospho-mutants clones showed significant increase in cell migration and tumorigenicity as compared with K8 wild type clones. Furthermore, loss of K8 Ser73 and Ser431 phosphorylation was also observed in human OSCC tissues analyzed by immunohistochemistry, where their dephosphorylation significantly correlated with size, lymph node metastasis and stage of the tumor. Our results provide first evidence of a potential role of K8 phosphorylation in cell migration and/or tumorigenicity in OSCC. Moreover, correlation studies of K8 dephosphorylation with clinico-pathological parameters of OSCC patients also suggest its possible use in prognostication of human OSCC.
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