Introduction
Hepatocellular carcinoma (HCC) is the second leading cause of
cancer‐related deaths worldwide 1. The disease is
often diagnosed at an advanced stage and progresses rapidly. Therefore,
early diagnosis is very important to improve the prognosis of patients.
Currently, early clinical screening methods involve serum alpha
fetoprotein (AFP) detection and liver ultrasound examination2. However, the sensitivity and specificity of markers
such as AFP are marginal 3. Additionally, ultrasound
examination relies heavily on the subjective judgment of the operator,
and conventional ultrasound often does not give results which can be
used to conclusively identify liver lesions. Therefore, there is an
urgent need to find more effective and accurate methods for screening
for liver cancer. As the understanding of tumor biology improves, liquid
biopsy will become an increasingly useful tool for early diagnosis. Risk
factors for primary liver cancer include hepatitis B virus (HBV) or
hepatitis C virus (HCV) infection, aflatoxin B intake, alcohol
consumption, cirrhosis and others. Among these risk factors, HBV and HCV
infections are the most significant, with viral hepatitis (HBV and HCV
infections) accounting for 90% and 40% of liver cancer incidence in
developing and developed countries, respectively.
To date, few studies have been conducted to assess the factors leading
to liver cancer in HCV patients. At present, HCV RNA, cirrhosis and HCV
genotype are thought to affect the occurrence of HCV-related liver
cancer, but these factors have not been conclusively proven. At present,
180 million people are chronically infected with HCV, which has been
reported to cause more than 350,000 deaths annually 4.
Epidemiological studies also indicate that HCV is associated with a
number of extrahepatic manifestations including insulin resistance, type
2 diabetes mellitus, glomerulopathies, oral manifestations and others5-7.
It has been demonstrated that 55% to 85% of new HCV-infected patients
will develop chronic hepatitis C, and 20% to 30% of chronically ill
patients will develop cirrhosis and liver failure 8.
Over the course of 30 years, 1% to 3% of patients with HCV without
cirrhosis will eventually develop HCC 9,10. Studies
have shown that one-third of HCC cases are caused by hepatitis C11. At present, there are three major known mechanisms
for HCV-induced HCC: direct pathways involving HCV core proteins,
indirect pathways caused by oxidative stress and steatosis, and microRNA
(miRNA)-related pathways 12. Previous studies have
shown that while biological signaling systems are complex, the analysis
of linear pathways can still provide valuable insights13.
In this study, we integrated multiple resources, including KEGG
pathways, known disease genes, miRNAs and differentially expressed
genes, to identify regulatory pathways and key regulators in HCV and HCC
from curated trans factor and miRNA regulatory networks. This analysis
revealed that EZH2 and hsa-miR-155-5p are critical genes
in the development of hepatocellular carcinoma. These genes and pathways
may be important biomarkers for predicting HCV-induced HCC. The workflow
of our study is shown in Fig. 1.