**1. Introduction**

Selenium (Se) is a naturally occurring essential micronutrient which had been received considerable attention in medicine and biology. As an essential component for mammalian cellular function, for the synthesis of several antioxidant enzymes, such as glutathione peroxidase, and for the synthesis of selenoproteins, selenium not only plays a vital role in balancing the redox environment in the body, but also is related to the prevention of diseases related to free radical damage, including infectious diseases, cancer, and cardiovascular diseases [1, 2]. The relationship between selenium and health has been the focus of medical community [3]. While

early observational studies have shown that the trace element selenium in the environment is closely related to the occurrence and development of tumors [3]. The incidence of cancer in patients with selenium deficiency is significantly increased, and the amount of selenium in the body is negatively correlated with cancer [4]. Furthermore, while some studies suggested selenium supplementation reduces the risk of cancer, some methodologically sound trials suggested selenium supplementation does not reduce the risk of cancer and may even increase it for some types, including advanced prostate cancer and skin cancer [5, 6]. An increased risk of diabetes has also been reported [7]. The relationship between selenium and cancer has been one of the most heated debates in human health over the past few decades. Moreover, the potential effect of selenium in the prevention and treatment of HCC is worthy of further investigation.

Primary liver cancer (PLC) is one of the most prevalent malignancies worldwide, and its incidence ranks fourth among all malignancies in China [8, 9]. The overall prognosis for patients with PLC is unsatisfactory with a 5-year survival rate of about 18%, and its mortality rate ranks the third in tumor-related death [10]. HCC is the most prevalent pathological type of PLC, accounting for about 85–90% of all PLCs [11]. Among all HCC patients, approximately 70–90% of them presented with a history of chronic liver diseases and cirrhosis [12]. While the primary risk factors for developing cirrhosis include chronic hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease, and nonalcoholic steatohepatitis (NASH), some other risk factors for HCC include uptake of aflatoxin-contaminated food, diabetes, obesity, certain genetic diseases such as hemochromatosis and some metabolic disorders [9, 11, 13]. Also, geographical factors have a direct impact on the various etiological features of HCC patients and make HCC an extremely complex condition associated with poor prognosis.

Epidemiology studies have found that the geographical factors and specific environmental exposures may be associated with HCC [14]. Inconsistent with the world's selenium distribution patterns, previous epidemiological studies have highlighted the particular relevance of selenium-associated cancer risk to the region of low selenium distribution, such as Asia or Africa [5, 15]. Some earlier surveying studies found that low environmental selenium is associated with certain cancers in the digestive system, and selenium supplementation may provide some cancer prevention effect [16]. However, the results had been inconsistent throughout various studies. Previous intervention trials in regions with low environmental selenium have shown a beneficial effect of selenium supplementation for cancer patients, while in most parts of North America, where there is sufficient environmental selenium, supplemental intake of selenium appears to be unrelated to chemoprevention [5, 17].

In Qidong, Jiangsu province, China, there is a high incidence of HCC and low environmental selenium level [18]. Various studies carried out in the region unraveled the negative correlation of HCC mortality with serum selenium level and environmental selenium level [19, 20]. However, in other areas in the world with low environmental selenium level, such correlation was not observed, suggesting that selenium deficiency may not be the sole cause of liver cancer and other factors, such as environmental carcinogens, the of heavy industry, chemical industry, etc. may collaboratively contribute to the high incidence of HCC [4].

Since the 1970s, continuous efforts had been made on studying the potential anti-cancer effect of selenium supplementation. Decrease of serum selenium level has also been observed in patients with chronic liver diseases. Mechanically, selenium plays a vital role in maintaining healthy liver function and synthesis of essential liver enzymes [21, 22]. Selenium protects the liver mainly in the following aspects: (1) reduces the damage of toxic substances in the environment to the liver;

*Selenium in the Prevention and Treatment of Hepatocellular Carcinoma: From Biomedical… DOI: http://dx.doi.org/10.5772/intechopen.88960*

(2) protects the integrity of the liver cell membrane by scavenging free radicals and preventing lipid peroxides through glutathione peroxidase; (3) accelerates the catabolism of ethanol, protecting the liver from alcoholic damage; and (4) stimulates both the humoral and cellular immunity and enhances immune function against hepatitis virus. The present article reviews the roles of selenium in HCC.

## **2. The preventive role of selenium in HCC tumorigenesis**

One of the most recognized roles of selenium is to prevent cancer. Since the 1970s, the tumorigenesis prevention role of selenium has also been studied in various chemical carcinogen-induced HCC models; for example, selenium can significantly suppress liver cancer carcinogenesis induced by aflatoxin B1, dimethyl azobenzene, or acetylamino. Consumption of food with Aflatoxin B1 (AFB1) contamination is one of the leading causes of liver cancer. In 1985, Milks, et al. investigated the effect of selenium on aflatoxin hepatocarcinogenesis in the rat model and found that oral supplementation of selenium can dose- and timedependently reduces aflatoxin B1-induced γ-GT variant hepatocyte foci and tumor nodules in rat liver [23]. Similarly, another animal study by Lei et al. in 1990 also found that selenium supplementation had an inhibitory effect on the initiation and promotion stages of AFB1-induced preneoplastic foci and nodules in HCC model without evidence of toxicity [24]. Further study showed that oral supplementation of selenium could dose- and time-dependently reduces aflatoxin B1-induced γ-GT variant hepatocyte foci and tumor nodules in animal models. Shi et al. demonstrated that selenium could reduce the amount of AFB1-DNA binding and effectively inhibit AFB1-induced DNA damage [25]. The main reason may be that AFB1 binds to glutathione (GSH) under the catalysis of the glutathione-S-converting enzyme (GSTS) and is excreted in a non-toxic form, thereby reducing the formation of AFB1-DNA compounds.

Diethylnitrosamine (DENA)-induced and phenobarbital (PB)-promoted HCC model is one of the most popular chemically induced HCC models used [26]. Thirunavukkarasu et al. conducted various studies investigating the chemopreventive properties and biochemical mechanisms of sodium selenite supplementation in the DENA-initiated and PB-promoted HCC rodent model with four parts per million (p.p.m.) of sodium selenite in drinking water for 14 weeks. Selenium supplementation elevates malate dehydrogenase level, a vital enzyme of the citric acid cycle [27]; increases superoxide dismutase (SOD and catalase (CAT) levels, two key antioxidant enzymes [28, 29]; decreases glutathione transferase (GST) level [30]; decreases alanine transaminase (AST), aspartate transaminase (ALT), and lactate dehydrogenase (LDH) elevations [31]; suppresses the elevated glycoprotein levels of glycoproteins such as globulin and hexosamine [32]; elevates ATPase enzymatic level and alters serum mineral levels [33, 34]; as well as increases vitamins C and E [35] in the DENA-initiated and PB-promoted HCC rodent model.

A more recent study by Liu et al. investigated the effects of selenium-enriched malt (SEM) on hepatocarcinogenesis, paraneoplastic syndrome, the hormones regulating blood glucose, vascular endothelial growth factor (VEGF), and several relevant angiogenic cytokines in DENA-induced HCC rat model [36–38]. The results showed that SEM decreased several liver enzyme levels, including alanine aminotransferase (ALT), alkaline phosphatase (ALP), as well as gamma-glutamyltranspeptidase (GGT); increased glucose levels and reduced hypoglycemia; and inhibited the angiogenesis by downregulating the expression of VEGF and interacted with tumor necrosis factor-alpha (TNF-α) and insulin-like growth factor II (IGF-II), and nitric oxide (NO). These results suggested that SEM may delay the

development of hepatocarcinoma in DENA-induced HCC rat model and partially by the inhibition of angiogenesis [38].

Other preclinical animal models had also been used to study the effect of selenium in liver cancer. Nine or thirteen weeks of sodium selenite (6 p.p.m) supplementation in drinking water prevented the azo dye (3′-MeDAB) hepatocarcinogenesis in male Sprague-Dawley rats [39, 40]. Supplementation with sodium selenite or selenomethionine reduces the focal volume and lower GST level in 2-acetylaminofluorene (2-AAF)-induced hepatocarcinogenesis rat model [41–43]. Sodium selenite suppressed the BOP-induced HCC in Syrian hamsters and induced apoptosis and caspase-3 level [44]. In the transgenic mice model, selenium supplementation also demonstrates anti-hepatocarcinogenesis effect. For example, in CBA mice, prenatal administration of selenium significantly decreased the spontaneous liver tumorigenesis [45]; in TGF-α/c-Myc transgenic mice, dietary selenium supplementation inhibited hepatocarcinogenesis, promoted apoptosis, and suppressed cell proliferation [46]; in Mdr2 knock-out mice, selenomethionine suppressed the development of HCC by regulating various genes involved in inflammation and oxidative stress [47]. In HCC xenograft, selenium-enriched green tea extracts also showed a suppressive effect in human hepatoma HepG2 cell mice xenograft model [48]. These results suggested that selenium holds a significant promising role as a potential anti-cancer agent *in vivo* in various liver cancer models.

## **3. Anti-cancer effect of selenium and the potential underlying mechanism**

Since the 1970s, the potential anti-tumor effects of selenium have attracted considerable research attention. In vitro studies have shown proliferation inhibitory role of selenium in liver cancer, colon cancer, gastric cancer, etc. [49, 50]. Various *in vivo* and *in vitro* studies have revealed its promising anti-tumor role breast cancer, lung cancer, colorectal cancer, etc. [51, 52]. These results suggest the broad-spectrum anti-cancer effect of selenium. In recent decades, increasing studies have investigated the potential role of selenium in liver cancer, involving several major cancer-associated signaling pathways, metabolic pathways, and transcription factors.
