Introduction
Primary liver cancer remains one of the leading causes of cancer death and is a major public health problem all over the world. It was reported that the incidence rate of primary liver cancer continued to increase, and there were 42,220 estimated new primary liver cancer cases yearly in the USA [
1]. However, the incidence rate of liver cancer was predicted to decrease in most Asian countries, except for Thailand [
2]. Hepatocellular carcinoma (HCC) is the major pathological type of primary liver cancer. The mortality and incidence rates of HCC remain high in Southeast Asia and Africa, where the infection of hepatitis B virus is endemic [
3,
4]. Most cases of HCC in these areas are secondary to chronic liver cirrhosis. In contrast, the HCC incidence rate is relatively low in Europe, Australia, and North America, where the major etiologies are chronic alcoholism, iron storage disorder and exposure to aflatoxin [
5].
Although the remarkable improvements are achieved in the treatment of HCC such as liver transplantation, radical surgical resection, and interventional therapy [
6‐
8], the long-term survival rates of HCC still remain low worldwide. One of the major reasons is that most patients with HCC were diagnosed at advanced stages. It is crucial to find out new therapeutic targets and novel diagnostic biomarkers for the early diagnosis and timely treatment of HCC. Therefore, it is still urgent to further explore the exact molecular mechanisms of the development, progression, invasion, and metastasis of HCC.
An increasing number of studies have revealed that the initiation of HCC was a complicated process that associated with multiple cellular pathways and numerous genes alterations [
9‐
11]. In addition, Gene Expression Omnibus (GEO) is a public functional genomics data repository that offers us an opportunity to mine the gene expression profiles of all kinds of cancers. Therefore, in this study, we tried to identify and evaluate the clinical values of the potential key genes in the occurrence of HCC by comparing the expression profiles of very early HCC tissue with that of chronic cirrhotic tissue samples by integrating the bioinformatics analysis.
Discussion
Although the initiation and progression of HCC had been investigated increasingly in recent years, the exact molecular mechanism of hepatocarcinogenesis is still unclear. In addition, the mortality of HCC remains high worldwide because of the limited therapeutic strategies. Thus, it is particularly urgent to dig deeper to find out the exact mechanisms underlying the development of HCC. Herein, bioinformatics analysis of gene expression profiles obtained from HCC may help us better to understand the molecular mechanism of tumor formation and even to find novel targets for cancer therapy. Bioinformatics analysis of HCC had been investigated in previous studies [
15‐
17]. However, these studies were mainly focused on comparing the gene expressions between benign liver tissue samples and HCC tissue samples at early or advanced stages. Rare studies devoted to finding out the differences between very early HCC tissue samples and benign liver diseases at the gene level, which might be helpful to understand the tumor formation.
In this study, we identified a total of 118 DGEs between very early HCC and cirrhotic tissue samples chosen from the GSE63898 expression profile datasets. GO and KEGG enrichment analyses of these DGEs were also performed in DAVID datasets. The results show that the identified DGEs were closely associated with several biological processes and components, such as negative regulation of growth, extracellular region, and immunoglobulin receptor binding. Moreover, these DGEs were significantly enriched for the p53 signaling pathway, chemical carcinogenesis. Furthermore, to analyze the interactional relationships between the DGEs, a PPI network was constructed and modules analysis was done.
We had also screened out eight hub genes including CDKN3, CDK1, CCNB1, TOP2A, CCNA2, CCNB2, PRC1, and RRM2. These hub genes had been investigated extensively in the previous researches. CDKN3, also known as KAP, CDI1, CIP2, and KAP1, encodes a dual specificity protein phosphatase that had reported to dephosphorylate CDK2. CDKN3 had been overexpressed frequently in several types of cancers, such as breast cancer, prostate cancer, and HCC [
18‐
20]. It had been reported that the overexpression of CDKN3 was correlated with the poor survival in cancer patients [
18]. In this study, we found that the overexpression of CDKN3 also had significantly effect on the overall survival of HCC patients. CDK1, a member of the Ser/Thr protein kinase family, plays an essential role in the G1/S and G2/M phase transitions of eukaryotic cell cycle by interacting with CCNB1 [
21]. In gastric carcinoma, high expression of CDK1 had found to lead to poor prognosis and correlated inversely with p27 expression [
22]. The overexpression of CDK1 was also found to be directly associated with portal invasion, high alpha-fetoprotein level, and poor prognosis in HCC [
23], which was in agreement with the results in this study.
TOP2A, encoding DNA topoisomerase II alpha, is involved in processes such as chromatid separation, cell cycle progression and the relief of torsional stress. TOP2A was reported to be frequently co-amplified with HER-2 and then reduce the clinical outcome in urinary bladder cancer and breast cancer [
24,
25]. Moreover, TOP2A was also found to be significantly overexpressed and linked with poor prognosis in HCC in this study, which was in conformity with results of previous studies [
26,
27]. CCNA2 protein is functioned as a regulator of the cell cycle by activating cyclin-dependent kinases. The expression of CCNA2 was driven by E2Fs [
28]. The aberrant expression of CCNA2 could be detected and closely related to reduced survival in HCC and breast cancer [
28,
29]. CCNB2 is also a member of the cyclin family, which are core components for cell cycle control. CCNB2 was found to be overexpressed and then result in poor prognosis in non-small-cell lung cancer and invasive breast carcinoma [
30,
31].
PRC1 is necessary for microtubules organization and is a substrate of several cyclin-dependent kinases. PRC1 was reported to involve in Wnt/β-catenin signaling pathway and then promote cancer proliferation and tumorigenesis in kinds of cancers, such as HCC and lung adenocarcinoma [
32,
33]. RRM2 plays a critical role in converting ribonucleotides to deoxynucleotides in DNA synthesis. The elevated expression of RRM2 may lead to the poor prognosis for patients with non-small cell lung cancer by stabilization of Bcl-2, which is a critical regulator of apoptosis [
34]. In addition, it had been shown RRM2 might be a novel therapeutic target in variety of cancers, such as breast cancer, non-small cell lung cancer, and bladder cancer [
34‐
37].