癌基因SKP2与人类恶性肿瘤

SKP2是新近发现的一种癌基因,是泛素连接酶(SCF)复合体的底物识别序列,对细胞周期起调控作用,与多种恶性肿瘤的发生、发展密切相关,现就SKP2与人类恶性肿瘤的关系简要综述。

Oncogenic Role of Skp2 and p27^(Kip1) in Intraductal Proliferative Lesions of the Breast

Objective To investigate whether the connection of p27 Kip1 to S-phase kinase-associated protein 2 (Skp2) plays an oncogenic role in intraductal proliferative lesions of the breast. Methods Here we investigated the mechanism involved in association of Skp2's degradation of p27 Kip1 with the breast carcinogenesis by immunohistochemical method through detection of Skp2 and p27 Kip1 protein levels in 120 paraffin-embedded tissues of intraductal proliferative lesions including usual ductal hyperplasia (UDH, n=30), atypical ductal hyperplasia (n=30), flat epithelial atypia (FEA, n=30), and ductal carcinoma in situ (DCIS, n=30). Moreover, the expression status of Skp2 and p27 Kip1 in 30 cases of the normal breast paraffin-embedded tissues were explored. Results The DCIS group was with the highest Skp2 level and the lowest p27 Kip1 level, and the UDH group was with the lowest Skp2 level and the highest p27 Kip1 level. Both Skp2 and p27 Kip1 levels in the DCIS group were significantly different from those in the UDH group (all P<0.01). The levels of Skp2 and p27 Kip1 in the FEA group were significantly different from both the DCIS and UDH groups (all P<0.05). p27 Kip1 was negatively correlated with Skp2 in both the UDH group (r=-0.629, P=0.026) and DCIS group (r=-0.893, P=0.000). Conclusion Overexpression of Skp2 might be the mechanism underlying p27 Kip1 over degradation.

Epidermal growth factor upregulates Skp2/Cks1 and p27^(kip1) in human extrahepatic cholangiocarcinoma cells

AIM:To evaluate the expression status of S-phase kinase-associated protein 2(Skp2)/cyclin-dependent kinases regulatory subunit 1(Cks1)and p27kip1,and assess the prognostic significance of Skp2/Cks1 expression with p27kip1in patients with extrahepatic cholangiocarcinoma.METHODS:Seventy-six patients who underwent curative resection for histologically confirmed extrahepatic cholangiocarcinoma at our institution from December1994 to March 2008 were enrolled.Immunohistochemical staining for Skp2,Cks1,p27kip1,and Ki67,along with other relevant molecular biologic experiments,were performed.RESULTS:By Cox regression analyses,advanced age(>65 years),advanced AJCC tumor stage,poorly differentiated histology,and higher immunostaining intensity of Skp2 were identified as independent prognostic factors in patients with extrahepatic cholangiocarcinoma.Exogenous epidermal growth factor(EGF,especially 0.1-10 ng/mL)significantly increased the proliferation indices by MTT assay and the mRNA levels of Skp2/Cks1 and p27kip1in SNU-1196,SNU-1079,and SNU-245 cells.The protein levels of Skp2/Cks1(from nuclear lysates)and p27kip1(from cytosolic lysate)were also significantly increased in these cells.There were significant reductions in the protein levels of Skp2/Cks1and p27kip1(from nuclear lysate)after the treatment of LY294002.By chromatin immunoprecipitation assay,we found that E2F1 transcription factor directly binds to the promoter site of Skp2.CONCLUSION:Higher immunostaining intensity of Skp2/Cks1 was an independent prognostic factor for patients with extrahepatic cholangiocarcinoma.EGF upregulates the mRNA and protein levels of Skp2/Cks1and p27kip1via the PI3K/Akt pathway and direct binding of E2F1 transcription factor with the Skp2 promoter.

Skp2蛋白和PTEN蛋白在子宫内膜疾病中的表达及相关性研究

目的探讨Skp2和PTEN在子宫内膜组织中的表达及其在子宫内膜癌发生、发展过程中的作用及两者的关系。方法采用免疫组织化SP法检测42例子宫内膜癌、35例子宫内膜不典型增生,23例复杂性增生及15例正常内膜中Skp2蛋白和PTEN蛋白的表达情况,并分析两者的相关性。结果子宫内膜癌中Skp2蛋白表达水平显著高于正常子宫内膜、复杂增生及不典型增生的子宫内膜,差异有显著性(P<0.05);PTEN蛋白的表达完全相反,且二者的表达呈负相关。结论Skp2蛋白和PTEN蛋白在子宫内膜癌的发生、发展中发挥重要作用,Skp2和PTEN的联合检测有助于判断子宫内膜癌的恶性程度和预后。

Molecular mechanism of Skp2 in promoting cervical cancer HeLa cell proliferation

Objective: To explore the impact of s-phase kinase-associated protein 2 (Skp2) on cervical cancer cell proliferation and the relationship between Skp2 and expression of cell regulation factors and transcription factors. Methods: RNAi technology was used to silence Skp2 gene in HeLa cells. After interference, RT-PCR was used for detection of Skp-2 mRNA, and Western blotting and flow cytometry were used for protein expression analysis. Results: siRNA significantly inhibited HeLa cell proliferation (P<0.05) and increased HeLa apoptosis, and G1/G0 phase cells were increased significantly (P<0.01). Skp2 siRNA transfected HeLa cells effectively reduced Skp2 protein levels, while p27 and p-p53 protein levels were increased significantly. RT-PCR results showed that after interference Skp2 mRNA, c-myc mRNA and cyclin A mRNA expressions decreased significantly compared with those in control group (P<0.01), and p27mRNA expression level was significantly higher (P<0.01). Conclusion: The change of Skp2 expression affects the expression of the cell cycle protein, thus affecting proliferation and apoptosis of HeLa cells. Skp2 protein plays an important role in the progression of cervical cancer; yet the specific mechanism still needs further study.

Correlation of BRD4 and Skp2 expression levels in ultrasound-guided thyroid nodule fine needle aspiration biopsy tissue with the pathological features of nodules

Objective:To study the correlation of bromodomain-containing protein 4(BRD4)and S-phase kinase-associated protein 2(Skp2)expression levels in ultrasound-guided thyroid nodule fine needle aspiration biopsy tissue with the pathological features of nodules.Methods:The tissues obtained in ultrasound-guided thyroid nodule fine needle aspiration biopsy in our hospital between March 2015 and March 2018 was selected and divided into malignant group and benign group according to the pathological results,and the expression levels of BRD4,Skp2,proliferation genes and angiogenesis genes were detected.Results:The BRD4 and Skp2 mRNA expression in thyroid nodules of the malignant group were significantly higher than those of the benign group,and the BRD4 and Skp2 mRNA expression in the malignant group of thyroid nodules with TNM III-IV,capsular invasion and lymph node metastasis were significantly higher than those in the thyroid nodules with TNM I-II,without capsular invasion and without lymph node metastasis;cyclin D1(CCND1),β-catenin,proliferation cell nuclear antigen(PCNA),vascular endothelial growth factor(VEGF),endothelial cell specific molecule-1(ESM-1),Survivin and cyclooxygenase 2(COX2)mRNA expression in thyroid nodules of the malignant group were obviously higher than those of the benign group and positively correlated with BRD4 and Skp2 while cyclin G2(CCNG2)and endostatin(ES)mRNA expression were significantly lower than those of the benign group and negatively correlated with BRD4 and Skp2.Conclusion:The high expression of BRD4 and Skp2 in malignant thyroid nodules is correlated with the pathological changes and can change the expression of proliferation genes and angiogenesis genes.