Brożyna Anna A, Aplin Andrew, Cohen Cynthia, Carlson Grant, Page Andrew Joseph, Murphy Michael, Slominski Andrzej T, Carlson J Andrew
Department of Tumor Pathology and Pathomorphology, Faculty of Health Sciences, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Oncology Centre - Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz 85-796, Poland.
Department of Cancer Biology, BLSB 524, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Oncotarget. 2017 Dec 23;9(3):4173-4187. doi: 10.18632/oncotarget.23648. eCollection 2018 Jan 9.
Cyclin-dependent kinase subunit 1 (Cks1) regulates the degradation of p27, an important G1-S inhibitor, which is up regulated by MAPK pathway activation. In this study, we sought to determine whether Cks1 expression is increased in melanocytic tumors and correlates with outcome and/or other clinicopathologic prognostic markers. Cks1 expression was assessed by immunohistochemistry in 298 melanocytic lesions. The frequency and intensity of cytoplasmic and nuclear expression was scored as a labeling index and correlated with clinico-pathological data. Nuclear Cks1 protein was found in 63% of melanocytic nevi, 89% primary and 90% metastatic melanomas with mean labeling index of 7 ± 16, 19 ± 20, and 30 ± 29, respectively. While cytoplasmic Cks1 was found in 41% of melanocytic nevi, 84% primary and 95% metastatic melanomas with mean labeling index of 18 ± 34, 35 ± 34, and 52 ± 34, accordingly. Histologic stepwise model of tumor progression, defined as progression from benign nevi to primary melanomas, to melanoma metastases, revealed a significant increase in nuclear and cytoplasmic Cks1 expression with tumor progression. Nuclear and cytoplasmic Cks1 expression correlated with the presence of ulceration, increased mitotic rate, Breslow depth, Clark level, tumor infiltrating lymphocytes and gender. However, other well-known prognostic factors (age, anatomic site, and regression) did not correlate with any type of Cks1 expression. Similarly, increasing nuclear expression of Cks1 significantly correlated with worse overall survival. Thus, Cks1 expression appears to play a role in the progression of melanoma, where high levels of expression are associated with poor outcome. Cytoplasmic expression of Cks1 might represent high turnover of protein via the ubiquination/proteosome pathway.
细胞周期蛋白依赖性激酶亚基1（Cks1）调节p27的降解，p27是一种重要的G1-S期抑制剂，其表达受丝裂原活化蛋白激酶（MAPK）信号通路激活的上调。在本研究中，我们试图确定Cks1在黑素细胞肿瘤中的表达是否增加，以及是否与预后和/或其他临床病理预后标志物相关。通过免疫组织化学法评估了298例黑素细胞病变中Cks1的表达情况。将细胞质和细胞核表达的频率和强度作为标记指数进行评分，并与临床病理数据相关联。在63%的黑素细胞痣、89%的原发性黑素瘤和90%的转移性黑素瘤中发现了细胞核Cks1蛋白，其平均标记指数分别为7±16、19±20和30±29。相应地，在41%的黑素细胞痣、84%的原发性黑素瘤和95%的转移性黑素瘤中发现了细胞质Cks1，其平均标记指数分别为18±34、35±34和52±34。肿瘤进展的组织学逐步模型（定义为从良性痣到原发性黑素瘤，再到黑素瘤转移）显示，随着肿瘤进展，细胞核和细胞质Cks1表达显著增加。细胞核和细胞质Cks1表达与溃疡、有丝分裂率增加、Breslow深度、Clark分级、肿瘤浸润淋巴细胞和性别相关。然而，其他众所周知的预后因素（年龄、解剖部位和消退）与任何类型的Cks1表达均无相关性。同样，Cks1细胞核表达增加与总体生存率较差显著相关。因此，Cks1表达似乎在黑素瘤进展中起作用，高水平表达与不良预后相关。Cks1的细胞质表达可能代表通过泛素化/蛋白酶体途径的蛋白质高周转率。
