Androgen pathway stimulates MicroRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis

Abstract

Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. By examining the expression of 22 HCC-related miRNAs between precancerous and cancerous liver tissues, we found miR-216a and miR-224 were significantly up-regulated, starting from the precancerous stage. Furthermore, the elevation of miR-216a was mainly identified in male patients. To study this gender difference, we demonstrated that pri-miR-216a is activated transcriptionally by the androgen pathway in a ligand-dependent manner and is further enhanced by the hepatitis B virus X protein. The transcription initiation site for pri-miR-216a was delineated, and one putative androgen-responsive element site was identified within its promoter region. Mutation of this site abolished the elevation of pri-miR-216a by the androgen pathway. One target of miR-216a was shown to be the tumor suppressor in lung cancer-1 gene (TSLC1) messenger RNA (mRNA) through the three target sites at its 3 0 untranslated region. Finally, the androgen receptor level increased in male liver tissues during hepatocarcinogenesis, starting from the precancerous stage, with a concomitant elevation of miR-216a but a decrease of TSLC1. Conclusion: The current study discovered the up-regulation of miRNA-216a by the androgen pathway and a subsequent suppression of TSLC1 as a new mechanism for the androgen pathway in early hepatocarcinogenesis. (HEPATOLOGY 2012;56:632-643) T he incidence of hepatocellular carcinoma (HCC) ranks fifth for cancers worldwide and causes about half a million deaths every year. 1 HCC is usually the ultimate outcome of chronic hepatitis caused by persistent viral infection (hepatitis B or C virus [HBV/HCV]) or by alcoholic/metabolic etiologies. After decades of chronic hepatitis, which might induce persistent necrosis and regeneration and accumulate the carcinogenic events in the hepatocytes, about 30%-40% of patients will progress into liver cirrhosis, and those will subsequently develop HCC with an annual incidence around 1%-5%. 2 Due to the multistep characteristic of cancer development, on average six to seven successive mutations are generally believed to be required to convert a normal hepatocyte into an invasive HCC. 3 As every mutation contributes to the formation of an expanded clone and thus presents a larger target population of cells for the next mutation, the cells surrounding the HCC could be considered precancerous cells, retaining the potential to become the subsequent HCC. 4 This

Predictors of hepatitis B e antigen‐negative hepatitis in chronic hepatitis B virus‐infected patients from childhood to adulthood

“…[30][31][32] Recent animal studies have shown that androgen increased HBV gene transcription, which was repressed by the estrogen pathway. [33][34][35] Serum testosterone level in chronic HBV-infected males was also associated with the severity of hepatocyte damage in our previous study. 36 The difference in HBeAg-negative hepatitis risk between genders is potentially linked to differences in risks of chronic liver insufficiency, liver cirrhosis, and hepatocellular carcinoma.…”

“…seroconversion at [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][30][31][32][33][34][35][36][37][38][39][40], and >40 years of age, respectively. 5,6 These differences may be attributable to differences in the studied cohorts.…”

Androgen receptor in hepatocarcinogenesis: Recent developments and perspectives

“…In previous studies that also analyzed control tissues, a higher AR expression was evident in tumoral tissues compared with peritumoral tissues, revealing that the disruption in AR homeostasis was associated with the incidence of HCC (15,18). Overexpression of AR in HCC cells may lead to the dysregulation of several molecules associated with cellular proliferation, tumor growth and/or metastasis (21,22,25). Findings from clinical HCC specimens revealed that an elevation in the levels of microRNA (miR)-216a and cell cycle-related kinase (CCRK) was positively correlated with an increase in the AR protein level, and that the overexpression of miR-216a and CCRK was associated with poor patient prognoses (18,25).…”

“…Overexpression of AR in HCC cells may lead to the dysregulation of several molecules associated with cellular proliferation, tumor growth and/or metastasis (21,22,25). Findings from clinical HCC specimens revealed that an elevation in the levels of microRNA (miR)-216a and cell cycle-related kinase (CCRK) was positively correlated with an increase in the AR protein level, and that the overexpression of miR-216a and CCRK was associated with poor patient prognoses (18,25). By contrast, Ma et al (22) established that AR overexpression was only present in tumors with a size of <3 cm (22).…”

“…However, the mechanism through which a disturbance in cellular miRNAs affects HCC initiation and progression remains to be elucidated. A study by Chen et al (25) identified that ligand-stimulated AR was a regulator of miR-216a and lead to enhanced tumorigenesis. Furthermore, these authors revealed that the level of miR-216a was significantly higher in male HCC patients (25).…”