The androgen receptor AR is a ligand dependent transcription

The androgen receptor (AR) is a ligand-dependent transcriptional factor that belongs to the nuclear receptor superfamily. Androgen/AR signals play important roles in normal liver function and in the development of liver diseases including HCC (Ma et al., 2014). Previous studies revealed a male predominance in HCC, which suggested that androgen/AR signals may promote hepatocarcinogenesis (Yeh and Chen, 2010). However, the results from several clinical trials using various anti-androgens to treat HCC remain controversial (Groupe d\'etude et de traitement du carcinome, H., 2004; Matsuura et al., 1994; Chao et al., 1996). Interestingly, Ma et al. revealed that AR might suppress advanced-stage HCC metastasis using liver-specific deletion of AR (L-ARKO) mice model and in vitro HCC cell lines, and over-expressing AR with Sorafenib treatment could better suppress the HCC progression at late stages (Ma et al., 2012). How to identify a potential molecule to increase AR expression in order to enhance Sorafenib chemotherapy efficacy, however, remains to be further elucidated. The microRNAs (miRNAs or miRs) are a group of small (around 22 nucleotides), non-coding RNA gene products existing in many organisms that play crucial post-transcriptional regulatory roles in mRNA translation and degradation by complementary alk5 pairing, predominantly in the 3′-untranslated region (3′UTR) (Lau et al., 2001). The discovery of miRNAs has increased our understanding of the post-transcriptional regulation of genes and how this contributes to diverse physiological, developmental, and pathophysiological processes, including cancer initiation and progression (Wang et al., 2012). Several studies have linked deregulation of miRNA expressions to HCC carcinogenesis and metastasis in recent years (Budhu et al., 2008; Salvi et al., 2013). Thus, miRNAs may become promising candidates for therapeutic targets. For example, Miravirsen, a miR-122 inhibitor that is already used in clinical trials, was found to be safe and have no dose-limiting adverse events or escape mutations in the miR-122 binding sites of the HCV genome so far (Janssen et al., 2013). Here we found miR-367-3p, whose expression is down regulated in advanced HCC, might function as an invasion suppressor in advanced HCC via altering the MDM2/AR/FKBP5/PHLPP/(pAKT and pERK) signals.
Materials and Methods
Results
Discussion HCC represents the most common histological subtype among primary liver cancers and the leading cause of death among patients with cirrhosis, accounting for 70% to 85% of the total liver cancer burden worldwide (Perz et al., 2006; Alazawi et al., 2010). Increasing incidence of HCC around the world, especially in the United States and Central Europe, allows a more profound understanding of the cancer progression and propelled a rapid development of life-prolonging therapies. With advances in liver surgery and transplantation in the past few decades, curative treatment can now be offered to HCC patients with liver resection and regeneration if diagnosed early enough or those who meet the transplant criteria, yielding over 50% 5-year survival rate through the two surgical treatments (Asham et al., 2013). In the past years, efforts have been made to dissect mechanisms by which targeting AR could inhibit HBV- and carcinogen-induced early-stage HCC development (Wu et al., 2010). Nevertheless, clinical trials using various anti-androgens in the attempt to treat HCC have inconsistent conclusions (Groupe d\'Etude et de Traitement du Carcinome, 2004; Matsuura et al., 1994; Chao et al., 1996). Several hypotheses have been proposed to elucidate this riddle, such as the fact that most of the anti-androgen therapies were developed to reduce/antagonize androgens from binding to AR, but not to target AR itself. Recently, the dual roles of AR in HCC were demonstrated showing AR might function as a stimulator to promote HCC initiation and development at early stages, yet might function as a metastasis suppressor in the advanced stages of HCC, implying that targeting AR should be stage-dependent (Ma et al., 2012). Importantly, results from in vivo mouse model studies also indicated that increased AR expression with a moderate dose (5μM) of Sorafenib might result in higher efficacy of HCC suppression at late stages. Furthermore, supported by data from cell line studies in vitro, mouse model studies in vivo, bioinformatic analyses and human clinical evidences, the present study provides clearer evidences that AR indeed acts as a metastasis suppressor in late-stage HCC. It remains to be seen whether activation of AR through hormone stimulation is equal to lentiviral induction of AR expression, thus a clinical application of these findings could be beneficial for patients with late stages of liver cancer.