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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia.
- insulin-like growth factor
- liver cancer
- cancer stemness
1. Introduction
Hepatocellular carcinoma (HCC) accounts for about 75–85% of all primary liver cancer [1][2][1,2], which is one of the top five causes of cancer deaths worldwide [2]. HCC can develop from loss of cell cycle control in adult hepatocytes or progenitor cells. Several risk factors for developing HCC have been identified, including hepatitis virus infection, abnormal fatty acid metabolism, alcoholic liver disease, and toxins [1][3][4][1,3,4]. The dominant cause varies across different geographical areas [5].
In five main types of hepatitis virus (type A, B, C, D, and E), types B and C cause the most public health burden, as they are responsible for more than half number of HCC [6]. Moreover, according to an investigation on the global burden of viral hepatitis from 1990 to 2013, about 96% of the viral hepatitis-related mortality are caused by hepatitis B and C [7]. In 2015, around 257 million people had chronic hepatitis B virus (HBV) infection, and 71 million had hepatitis C virus (HCV) infection [8]. A goal of the World Health Organization’s Global Strategy for Viral Hepatitis Elimination in 2016 was to reduce hepatitis-related deaths by 65% by 2030 (from 1.34 million deaths annually to less than 0.5 million) [9].
Therapeutic strategies available for HCC, such as resection, transplantation, ablation, radiotherapy, chemotherapy, and molecular targeting therapy, are highly dependent on the stage of liver cirrhosis and on the offerings of the medical center, which varies among different countries [1][3][4][10][1,3,4,10]. Targeted therapies (sorafenib and lenvatinib) have been approved for patients with advanced HCC who are not eligible for local treatments. However, the median overall survival (OS) with either sorafenib or lenvatinib is only about 13 months [11][12][13][11,12,13]. Therefore, an improvement for targeted therapies is needed.
2. The Etiology of HCC
2.1. Virus Infections Initiate HCC
HCC is often associated with HBV and HCV. According to a 2016 report by the U.S. Centers for Disease Control and Prevention, approximately 65% of liver cancers are associated with the hepatitis B or C virus. In a study of 3843 patients in Taiwan, hepatitis viruses were associated with more than 80% of HCC [6].
HBV is a small DNA virus with a partially double-stranded DNA of 3200 bp [14][16]. HBV infection is responsible for 66% of virus-caused HCC deaths worldwide [8]. The highest prevalence of HBV infection is reported in the African (6.1%) and Western Pacific (6.2%) regions [8]. Most cases of HBV are transmitted through bodily fluids, such as via blood transfusion, sexual contact, or from mother to child. The HBV virus can amplify independently inside hepatocytes; integration of HBV into the hepatocyte genome can increase carcinogenic opportunities in HBV-infected patients.
The HBx gene is mainly responsible for HBV-associated HCC development. The HBV DNA contains four open reading frames (ORFs), which code for surface antigen (S) protein, precore (C) protein, polymerase (P) protein, and X proteins [15][16][17,18]. The ORF-X is the smallest ORF with 462 bp, and it acts as a viral production promotor within the cell [17][18][19,20]. Silencing the X gene results in the suppression of HBeAg production and viral production [19][20][21,22]. HBx exerts its effects on cell cycle progression and the normal physiology of hepatocytes by upregulating levels of G1 proteins [21][23]. In addition, HBx initiates HCC development by upregulating Ras/Raf/MAPK signaling, PI-3K/Akt signaling, Jak/STAT signaling, and NFκB signaling [16][22][18,24].
HBV perinatal transmission is more effective because the immune systems have not fully matured yet in fetus [23][25]. Acquisition of HBV in the early life causes chronic infection in most cases while infection in adults is usually recovered with subsequent acquired immunity [24][25][26][26,27,28]. A study of 1280 seronegative patients from 12 Yupik Eskimo villages in America demonstrated that the rate of chronic hepatitis B in HBV infected patients declined with increasing age. Percentages for the ≤4 years group, 5–9 years group, and adults (>30 years) group were 28%, 16.4%, and 7.7%, respectively [25][27]. Fortunately, there is a vaccine to prevent HBV infection that is effective for all ages including infants, children, and adults [8].
The HCV pandemic affects all regions worldwide; the highest prevalence occurred in Central Asia, East Europe, and central and Western Saharan of Africa [8][27][8,29]. Globally, there were 1.75 million new HCV infections and 57 million people living with chronic HCV in 2015 [8]. Approximately, 75% of patients with acute HCV infection progress to develop chronic HCV, and the risk of developing cirrhosis/HCC from chronic HCV is approximately 10–20% [28][29][30,31].
Unlike HBV, HCV is an RNA virus, which makes it difficult to insert into the hepatocyte genome. Therefore, its carcinogenic activity is linked to indirect mechanisms. The HCV relies on endoplasmic reticulum (ER) in the hepatocyte to produce viral proteins, thus causing the ER stress. The ER is an important organelle that helps to maintain normal functions of hepatocytes, such as the transportation of proteins and lipids and the synthesis of proteins [30][31][32][32,33,34]. As a result, injuring hepatocytes by HCV could lead to cirrhosis.
There is no effective HCV vaccine; however, effective HCV therapies are available and work well. Direct-acting antivirus (DAA) therapy was introduced in 2013 and became recommended first line treatment for HCV by WHO guidelines in 2014 [8]. DAA therapy can cure 95% of HCV infections [29][31].
Coinfection with both virus types raises the risk for cirrhosis progression [33][34][35,36], and cirrhosis progression is highly possible to lead to HCC initiation. Coinfected patients show a higher rate of cirrhosis than HBV mono-infected patients (44% vs. 21%) [35][37]. In addition, the percentage of cirrhosis and HCC in dual-infected patients is higher than in HCV mono-infected patients (95% vs. 48.5 and 63% vs. 15%, respectively) [36][38]. Coinfected patients were more often immigrants from Africa and Asia than HCV- or HBV-mono-infected patients (52% vs. 20% and 22%, respectively, p = 0.01) [34][36]. In addition, 2.7 million patients are coinfected with HBV-HIV and 2.3 million patients are coinfected with HCV-HIV [8]. Coinfection with HBV/HCV and HIV raises the risk of liver cirrhosis and HCC development [37][38][39][39,40,41]. The liver-related mortality rate of patients with HBV-HIV (14.2/1000) is higher than that of patients with only HIV (1.7/1000) or only HBV (0.8/1000) [37][39].
2.2. Obesity and NAFLD Cause HCC
Obesity is rapidly becoming a health problem all over the world, especially in Western countries. It is established that more than 2 billion people are overweight or obese worldwide. By the year 2030, it is projected that 38% of adults will be overweight and 20% will be obese if this trend is not changed [40][42]. It is well known that obesity is highly associated with other health problems such as cardiovascular disease, stroke, hypertension, and cancer. A meta-analysis of data from 1,779,471 individuals from articles published from 1996 to 2011 found a positive correlation between body mass index (BMI) and risk of liver cancer. Persons with a BMI of 25, 30, or 35 kg/m2 had a 1.02, 1.35, or 2.22 fold relative risk of liver cancer, respectively [41][43]. In a retrospective analysis of 714 patients with HCC who underwent curative hepatectomy, the 5-year OS rate of HBV-HCC patients with BMI ≥ 25 kg/m2 (65%) was lower than that of HBV-HCC patients with BMI < 25 kg/m2 (85%). However, among patients with HCV-HCC, those with BMI ≥ 25 kg/m2 had a better 5-year OS rate than those with BMI < 25 kg/m2 (75% vs. 65%) [42][44].
Recently, nonalcoholic steatohepatitis (NAFLD), which is caused by obesity and some hepatic histological damage, became the major cause of chronic liver disease in Western countries [43][45]. The risk of HCC developing in nonalcoholic steatohepatitis (NASH)-associated cirrhosis was 2.4–12.8% while that of HCC developing in NASH without cirrhosis was low (0–3%) [44][46]. Besides, a study, which compared 296,707 patients with NAFLD with 296,707 matched control, showed that the HCC incidence was significantly higher among NAFLD patients versus control (0.02/1000 person-years; hazard ratio, 7.62, 95% confidence interval = 5.76–10.09) [45][47]. Similarly, a data analysis from four databases which included 18,782,281 eligible individuals from United Kingdom, Netherlands, Italy, and Spain showed that patients with NAFLD/NASH had cirrhosis risk and HCC risk significantly higher than controls with pooled hazard ratios 4.73 (95% CI 2.43–9.19) and 3.51 (95% CI 1.72–7.16), respectively [46][48]. The data of 25,947 subjects in Korea from September 1, 2004, to December 31, 2005, indicated the NAFLD was associated with the development of HCC. The cancer incidence rate of patients with NAFLD was significantly higher than that of control (782.9 version 592.8/100,000 person-years; hazard ratio 1.32; 95%CI 2.09–133.85; p < 0.001) [47][49].
Furthermore, the risk of NAFLD-related HCC increased quickly in the last two decades. A study that included 323 HCC patients from 1995–1999 to 2010–2014, indicated that the prevalence of NAFLD-HCC increased from 2.6% to 19.5%, respectively, p = 0.003 [48][50]. In addition, among 158,347 adult liver transplant candidates in United State, the proportion of patients with HCC increased from 6.4% (2002) to 23% (2016) (trend p < 0.001) [49][51].
Together, these data suggest that the risk of HCC due to NAFLD is going more serious while that of HCC due to HCV/HBV infection is going better of control. However, until recently, there is no consensus on optimal HCC screening measures for patients with NAFLD/NASH.
2.3. Other Factors That Cause HCC
Aflatoxins, a group of mycotoxins produced by the fungi Aspergillus flavus and Aspergillus parasiticus, account for a large part of toxin-related HCC. People in tropical countries may ingest aflatoxin through fungal-contaminated food that was improperly stored in high humidity and temperature. Aflatoxin causes an arginine–to-serine mutation at codon 249 of the p53 gene, leading to cancellation of the tumor suppression functions of this gene. A study using HCC samples from high and low risk areas of aflatoxin showed that the third nucleotide guanine to thymine transversion mutation at codon 249 was present in 57% and 10% of samples, respectively [50][52]. Similarly, liver cancer cell lines that were induced to express high levels of CYP450 were more sensitive to the cytotoxic effect of aflatoxin than parental cells. The third nucleotide guanine to thymine transversions in the codon number 249 and the first nucleotide cytosine to adenine transversions at codon number 250 of p53 gene were found at a high frequency [51][53]. A high incidence of HCC is found in areas where aflatoxin and HBV infection are common, raising speculation regarding a synergic carcinogenic interaction between aflatoxin and HBV infection [52][54]. A study on HCC samples from Guangxi, China, confirmed the positive correlation between HCC and aflatoxin but evidence for an HBV-aflatoxin interaction modulating the p53 mutation [53][55] or for a hepatitis B surface antigen (HBsAg) and aflatoxin synergistic effect in HCC [54][56] was not clear.
Alcohol consumption, another risk factor for HCC, induces liver cancer development through steatosis, steatohepatitis, and cirrhosis. The acetaldehyde and lipid peroxidation from ethanol metabolism in the liver creates protein adducts and DNA adducts, which can trigger liver injury and fibrogenesis [55][56][57][57,58,59]. In addition, alcohol metabolism-derived ROS can destroy large organelles and alter the structure and function of DNA [58][60]. Oxidative stress in the liver promotes the secretion of cytokines and chemokines (IL-6, IL10, IL1β, and TNFα) [59][60][61][62][61,62,63,64] and activates several signaling pathways (Jak/STAT; NF-kB, and MAPK cascade) which are implicated in the initiation of HCC. Findings from a systematic review and meta-analysis indicate that the relative risks of liver cancer for moderate drinking (<3 drinks/day) and heavy drinking (≥3 drinks/day) are 0.91 and 1.16, in comparison to non-drinking. The study also found an estimated excess risk of 46% or 66% in drinkers who consumed 50 g or 100 g alcohol per day [63][65]. A projected prevalence study has predicted that, if current trends continue, deaths due to alcohol-related liver disease will increase from 8.23 deaths/100,000 person-years in 2019 to 15.20 deaths/100,000 person-years in 2040 [64][66].
