br Introduction Hepatocellular carcinoma HCC is the third

Introduction Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related death worldwide and accounts for 70–85% of all liver cancer diagnoses [1]. In East and South-East Asia, the occurrence of HCC and the related number of fatalities have gradually increased in recent decades [2], making it a significant public health burden. Advanced clinical treatment improves survival, but the 5-year survival rate for HCC patients remains relatively low [3], [4]. Further, the mortality rate of HCC patients remains considerably high because of late stage detection and development metastasis-associated diseases [5]. Risk factors of HCC include chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, cigarette smoking, and excessive alcohol consumption [6]. Moreover, genetic abnormalities have also been shown to play a crucial role in HCC development and pathogenesis. Unfortunately, while a number of studies have identified HCC-associated genes, our understanding of their underlying mechanisms related to HCC development and progression is limited. Thus, continued study of known HCC-associated genes as well as the identification of novel genetic factors is essential to enhance HCC treatment and patient outcome. Tripartite motif containing (TRIM) proteins display important functions in numerous biological processes, including cell proliferation, apoptosis, tumorigenesis, and tumor progression [7]. Upregulation of TRIM24, or intermediary factor 1-alpha (TIF1α), for example, has been reported to be associated with several types of cancer via various mechanisms. In gastric cancer tissue, increased TRIM24 expression appears to be related to the miR-511/TRIM24 axis, whereby TRIM24 is a direct target of miR-511 and plays a key role in tumorigenesis [8]. TRIM24 expression was also upregulated in cervical cancer [9], prostate cancer [10], GW2580 carcinoma [11], head and neck squamous cell carcinoma [12], non-small cell lung cancer [13], and breast cancer [14]. TRIM24 contains a really interesting new gene (RING) finger domain at the N-terminus, which is important for its E3 ubiquitin ligase function [15]. The C-terminal domain also enables TRIM24 to recognize unmodified histone H3 at lysine 4 (H3K4) and acetylated histone H3 at lysine 23 (H3K23) [14]. It is likely that the structure of this protein is related to the mechanism underlying its role in cancer pathogenesis. However, this mechanism is largely unknown, particularly in HCC. In this study, we investigated the role of TRIM24 in HCC and found that TRIM24 expression is increased in human clinical HCC samples. Its expression appears to promote the proliferation and migration of HCC cells in vitro and tumor development in vivo via the AMP-activated protein kinase (AMPK) signaling pathway. Taken together, these data indicate that TRIM42-AMPK signaling likely plays an important role in HCC progression and could be a novel clinical target for the treatment of HCC.
Materials and methods
Results
Discussion HCC is one of the most common causes of cancer-related deaths globally [18]. However, the exact mechanism underlying HCC progression remains unclear. In the present study, we provide evidence that TRIM24 expression is significantly increased in HCC clinical samples and is positively correlated with tumor stage. TRIM24 promotes HCC cell proliferation and migration in vitro and tumor progression in vivo. Mechanistically, TRIM24 appears to promote HCC through AMPK signaling pathways. These results indicate that TRIM24 expression in HCC clinical samples could be used as a potential indicator to predict HCC stage and progression, which could provide additional support for personalized therapy when combined with other diagnostics. The human HCC cell lines Huh7 and SMMC-7721 were used to explore the biological functions of TRIM24. We found that TRIM24 knockdown by RNA interference inhibits cell proliferation and migration of Huh7 cells, while TRIM24 overexpression in SMMC-7721 cells showed the opposite efforts. Our in vivo studies also demonstrated that TRIM24 promotes tumor progression, as evident from the observed decrease in tumor volume, tumor weight, Ki67 and PCNA expression in sh-TRIM24 tumors. Thus, these results indicate that TRIM24 promotes HCC progression, which is consistent with previous studies [19].