Clinical role and biological function of CDK5 in hepatocellular carcinoma: A study based on immunohistochemistry, RNA-seq and in vitro investigation.

Rui Zhang,Zhen-Bo Feng,Yi-Wu Dang,Peng Lin,Hong Yang,Yun He,Gang Chen

doi:10.18632/oncotarget.22659

Rui Zhang, Zhen-Bo Feng + Show 5 more

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https://doi.org/10.18632/oncotarget.22659

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Abstract

To investigate the clinical role and biological function of cyclin-dependent kinase 5 (CDK5) in hepatocellular carcinoma (HCC), 412 surgically resected tissue samples (HCC, n=171; non-HCC=241) were obtained and analyzed with immunohistochemistry. The diagnostic and prognostic values of CDK5 expression levels in HCC were clarified. Moreover, RNA-seq data or microarray datasets from The Cancer Genome Atlas (TCGA) (HCC, n=374; normal, n=50) or other public databases (HCC, n=1864; non-tumor=1995) regarding CDK5 in HCC were extracted and examined. Several bioinformatic methods were performed to identify CDK5-regulated pathways. In vitro experiments were adopted to measure proliferation and apoptosis in HCC cells after CDK5 mRNA was inhibited in the HCC cell lines HepG2 and HepB3. Based on immunohistochemistry, CDK5 expression levels were notably increased in HCC tissues (n=171) compared with normal (n=33, P<0.001), cirrhosis (n=37, P<0.001), and adjacent non-cancerous liver (n=171, P<0.001) tissues. The up-regulation of CDK5 was associated with higher differentiation (P<0.001), metastasis (P<0.001), advanced clinical TNM stages (P<0.001), portal vein tumor embolus (P=0.003) and vascular invasion (P=0.004). Additionally, TCGA data analysis also revealed significantly increased CDK5 expression in HCC compared with non-cancerous hepatic tissues (P<0.001). The pooled standard mean deviation (SMD) based on 36 included datasets (HCC, n=2238; non-cancerous, n=2045) indicated that CDK5 was up-regulated in HCC (SMD=1.23, 95% CI: 1.00-1.45, P<0.001). The area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve was 0.88. Furthermore, CDK5 knock-down inhibited proliferation and promoted apoptosis. In conclusion, CDK5 plays an essential role in the initiation and progression of HCC, most likely via accelerating proliferation and suppressing apoptosis in HCC cells by regulating the cell cycle and DNA replication pathways.

Highlights

Ranked as the fifth common type of cancer worldwide, hepatocellular carcinoma (HCC) ranks as the third cause of cancer-related deaths [1]
The area under the curve (AUC) of receiver operator characteristic curves (ROC) was 0.678 for cyclin-dependent kinase 5 (CDK5) protein to diagnose HCC, which indicated a certain value for clinical diagnosis of HCC
Remarkable overexpression of CDK5 protein was confirmed by the independent cases from Protein Atlas, which revealed the absence of CDK5 in normal livers and moderate-strong CDK5 staining in HCC (Figure 3)

Summary

Introduction

Ranked as the fifth common type of cancer worldwide, hepatocellular carcinoma (HCC) ranks as the third cause of cancer-related deaths [1]. HCC is characterized by its early invasion and diffuse metastases characteristics [3]. The lack of ideal biomarkers consistently leads to HCC diagnostic www.impactjournals.com/oncotarget delay. A majority of patients suffering from HCC are unable to obtain a definite diagnosis until advanced stage disease, making HCC one of the most frequent cancers worldwide [5]. Given its characteristics of toxicity and resistance to chemotherapy and radiotherapy, the prognosis of HCC remains poor to date [6,7,8]. The mortality rate of HCC is increasing despite significant progress in diagnosis and treatment obtained over the last few years. The 5-year survival rate of HCC is only 5% [9]. The identification of a target gene strongly associated with HCC is of great value for HCC prevention and diagnosis

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