Cyclin-Dependent Kinase Regulatory Subunit 2 Indicated Poor Prognosis and Facilitated Aggressive Phenotype of Hepatocellular Carcinoma.

Jie Zhang,Yuqing Xu,Lina Lu,Jinxia Liu,Qianqian Song,Wenjie Zheng

doi:10.1155/2019/8964015

Abstract

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a member of the cell cycle-dependent protein kinase subunit family, which is implicated as an oncogene in various malignancies. However, the clinical significance, oncogenic functions, and related mechanisms of CKS2 in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, expression features and prognostic value of CKS2 were evaluated in the bioinformatic databases and HCC tissues. The effects of CKS2 on the malignant phenotypes of HCC cells were explored in vitro. According to the analyses of three bioinformatic databases, mRNA levels of CKS2 were elevated in HCC tissues compared with the normal tissues. Immunohistochemical assays found that high CKS2 expression was closely associated with liver cirrhosis (P = 0.019), poor differentiation (P = 0.02), portal vein invasion (P < 0.001), TNM stage (P = 0.019), tumor metastasis (P = 0.008), and recurrence (P = 0.003). The multivariate regression analyses suggested that CKS2 was an independent prognostic factor for overall survival (HR = 2.088, P = 0.014) and disease-free survival (HR = 2.511, P = 0.002) of HCC patients. Moreover, the bioinformatic analyses indicated that CKS2 might be associated with the malignant phenotypes in HCC progression. In addition, in vitro assays showed that CKS2 expression was higher in HCC cell lines than in normal liver cells. Knockdown of CKS2 remarkably repressed the proliferation, colony formation (P = 0.0003), chemoresistance, migration (P = 0.0047), and invasion (P = 0.0012) of HCC cells. Taken together, overexpression of CKS2 was significantly correlated with poor prognosis of HCC patients and the malignant phenotypes of HCC cells, suggesting that it was a novel prognostic biomarker and potential target of HCC.

Highlights

Hepatocellular carcinoma (HCC), accounting for 85–90% of all primary liver cancers, is the sixth most common type of cancer as well as the third most frequent cause of cancerrelated deaths [1, 2]
Cyclin-dependent kinase regulatory subunit 2 (CKS2) mRNA Was Upregulated in Human HCC Tissues
Higher CKS2 mRNA levels were observed in HCC tissues compared with normal tissues in databases including the GSE14520 (Figure 1(b); fold change, 5.02; P < 0:001), GSE45436 (Figure 1(c); fold change, 4.36; P < 0:001), and GSE36376 (Figure 1(d); fold change, 2.07; P < 0:001)

Summary

Introduction

Hepatocellular carcinoma (HCC), accounting for 85–90% of all primary liver cancers, is the sixth most common type of cancer as well as the third most frequent cause of cancerrelated deaths [1, 2]. Liver transplantation and radiofrequency (thermal) ablation (RF(T)A) are commonly applied in HCC patients at early and intermediate stages [4,5,6]. A multiple tyrosine kinase inhibitor, is the only systemic agent approved by the FDA for the first-line treatment of unresectable HCC patients [7]. While various targeted drugs (regorafenib, lenvatinib, and nivolumab) have been adopted in the Disease Markers treatment paradigm, the long-term survival of patients with HCC remains poor [8,9,10]. It is of great importance to find novel prognostic biomarkers and a potential target for HCC

Methods

Results

Conclusion