Androgen receptor roles in hepatocellular carcinoma, fatty liver, cirrhosis and hepatitis

Abstract

Androgen/androgen receptor (AR) signaling plays important roles in normal liver function and in progression of liver diseases. In studies of noncancerous liver diseases, AR knockout mouse models of liver disease have revealed that androgen/AR signaling suppresses the development of steatosis, virus-related hepatitis, and cirrhosis. In addition, studies have shown that targeting AR in bone marrow-derived mesenchymal stem cells (BM-MSCs) improves their self-renewal and migration potentials, thereby increasing the efficacy of BM-MSC transplantation as a way to control the progression of cirrhosis. Androgen/AR signaling is known to be involved in the initiation of carcinogen- or hepatitis B virus-related hepatocellular carcinoma (HCC). However, studies have demonstrated that AR, rather than androgen, plays the dominant role in cancer initiation. Therefore, targeting AR might be an appropriate therapy for patients with early-stage HCC. In contrast, androgen/AR signaling has been shown to suppress metastasis of HCC in patients with late-stage disease. In addition, there is evidence that therapy comprising Sorafenib and agents that enhance the functional expression of AR may suppress the progression of late-stage HCC.

Keywords: androgen receptor (AR); hepatocellular carcinoma (HCC).

Figure 1

Androgen/AR roles in non-cancerous liver disease progression. In hepatitis virus (HBV and HCV)-related hepatic inflammation, androgen/AR promotes HBV virus replication, yet, AR might suppress the hepatitis process. On the other hand, AR also plays a suppressive role in the toxin-related liver inflammation process. Moreover, bone marrow-derived mesenchymal stem cells (BM-MSC) can infiltrate into the damage liver; however, AR suppresses the ability of BM-MSCs to repair liver damage.

Figure 2

Androgen/AR signaling in hepatocarcinogenesis. There are three major factors that contribute to the development of liver tumors, e.g., HBV, carcinogens, and cirrhosis. In HBV-related HCC, AR promotes HBV virus replication to increase viral titers, as well as viral antigens to positively feedback HBV replication. In carcinogen- and DEN-related HCC, AR suppresses p53 and related cellular oxidative stress and DNA damage repair, thereby promoting hepatocyte transformation. However, it is still unknown how AR is involved in cirrhosis-related HCC.

Figure 3

Novel therapeutic strategy targeting AR to battle liver diseases. In the early stage of HCC development, targeting AR using ASC-J9 might suppress early cancer progression. And in the cirrhotic liver, ASC-J9 applied to BM-MSC for autologus implantation might be effective against cirrhosis. At last, treatment of patients with advanced-stage HCC with Sorafenib and expressing AR in the liver might improve the therapeutic efficiency of Sorafenib at reducing the incidence of metastasis or recurrence.