**7. Epidemiological investigations and clinical trials**

Many studies have shown that the level of blood selenium in patients with chronic liver disease is reduced, and it can be corrected by selenium supplementation [67–69]. Selenium supplementation can inhibit the lipid peroxidation of immune cells in patients with liver diseases, regulate cellular immune function, and alleviate immunopathological damage. In the treatment of patients with chronic hepatitis, in the anti-viral, immune-modulating, and liver-protecting treatment, it is beneficial to correct the blood selenium level of hepatitis patients by detecting and conditioning so that lipid oxidation and liver repair could be resisted [12]. Selenium and selenium supplementation for the treatment of liver disease should attract the attention of the medical community. However, controversies remain with whether a relationship exists between serum selenium level and HCC risk.

Some pioneering studies performed in China in the 1990s showed that plasma selenium level is negatively correlated with the occurrence of HCC in areas with low environmental selenium level [19, 20]. A preliminary report by Yu et al. in 1991 of two intervention trials in high-risk populations of PLC with selenium supplementation in Qidong, Jiangsu province, China, showed that among individuals with a family history of PLC, oral supplementation of 200 mg selenium in the form of selenized yeast (Se-yeast) daily for 4 and 2 years, respectively, showed significant reduction in PLC incidence compared with placebo [19]. Another study by Yu et al. in 1997 of an interventional trial among 130,471 individuals living in Qidong Country showed that a reduction PLC incidence by 35.1% in selenite table salt supplemented group vs. the non-supplemented group after an 8-year follow-up. Consistently, an epidemiological study in Taiwan by Yu et al. involving a cohort of 7342 chronic carriers of hepatitis B and C virus male with an average of 5.3 years of follow-up showed an inverse association between plasma selenium levels and the risk of HCC among men with chronic hepatitis virus infection [70]. Another study in Korea by Kim et al. in 2012 also reported an apparent correlation between low plasma selenium level and incidence of HCC in Korean hepatoma patients [71]. However, no relationship was observed between plasma selenium concentration and incidence of HCC in a study with Japanese hepatoma patients [72]. In 2016, a systemic review meta-analysis involving 9 trials and a total of 1433 subjects supported an inverse correlation between Se level and the risk of HCC, and lowered Se level had a relationship with HCC with a remarkable heterogeneity (I2 = 74.3%, P < 0.001) [4]. However, epidemiological investigations and biological studies should be further conducted to demonstrate and verify whether selenium supplements are beneficial for the prevention and treatment of HCC and to elucidate its exact mechanism of action.

## **8. Discussion and conclusion**

Over decades, an increase in the trend of development of novel selenium nanoparticles and selenium-containing inhibitors aims to improve the therapeutic efficacy and relative potency of selenium. Experimental studies with animal tumor models and epidemiological studies of human tumors have revealed that selenium is one of the factors affecting the risk of cancer. The huge number of publications has suggested the potential role of selenium and redox-active selenium compounds as inhibitors and therapeutic agents for liver cancer. However, the studies are difficult to compare among different selenium compounds due to a high degree of variations on the effective dosage anti-proliferation due to the difference in the *ex vivo* culture condition.

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

Further, although some epidemiology studies have supported the hypothesis that selenium supplementation can reduce the risk of cancer, inconsistent results have also been reported. Another important aspect of being considered for the use of selenium-containing compounds in anticancer is as a chemical protective agent against toxic side effects of anticancer drugs. Selenium has also been reported to have a protective effect against cisplatin-induced nephrotoxicity without affecting its anti-tumor activity in rodent model [73]. Further trials are needed to confirm the selenium supplementation for liver cancer in terms of its effect on prognosis as well as potential toxic effect.

This chapter summarizes the pharmacological effects of selenium in HCC *in vitro* and *in vivo*, and to highlight the recently discovered molecular mechanisms, to outline the correlation of selenium level and the risk of HCC in patients, and to discuss the clinical application of selenium in HCC prevention and treatment. In conclusion, the preclinical studies presented in this chapter summarized the promise of selenium as a potential anti-cancer agent and presented the chemo-preventive role in HCC. Although substantial evidence for the anti-cancer effect of selenium is discussed, further studies are warranted.
