Abstract
Accumulating evidence indicates that hepatitis B virus X protein (HBx) plays a key role in HBV-related hepatocellular carcinoma (HCC) aggressiveness; however, the underlying mechanisms are not entirely clear. Long non-coding RNAs (lncRNAs), which participate in the regulation of diverse biological processes, may be critical for the function of HBx. Our research indicated that HBx induced changes in the expression of numerous lncRNAs and implicated the novel lncRNA RP11-241J12.3 in HBx-mediated HCC aggressiveness. Although RP11-241J12.3 expression was downregulated in transient HBx-expressing HCC cells (similar to the early stage of HBV infection), its oncogenic properties remained. The results showed that RP11-241J12.3 not only accelerated DNA synthesis and upregulated the expression of pyruvate carboxylase (PC) and MSH3, which is a key protein in pyruvate metabolism and DNA mismatch repair (MMR), but also promoted tumor growth in vitro and in vivo, thus promoting HCC aggressiveness. More importantly, we revealed that RP11-241J12.3 may interact with PC and identified its location in the cytoplasm close to the nucleus using fluorescence in situ hybridization (FISH). We also observed RP11-241J12.3 expression was upregulated in HCC tissues compared with the paracarcinomatous tissues. Furthermore, RP11-241J12.3 expression levels showed a close relationship with clinical stage and tumor size and that low RP11-241J12.3 expression was significantly correlated with longer HCC patient survival. These results further our understanding of the lncRNAs regulated by HBx in HCC, and provide evidence that dysregulation of RP11-241J12.3 contributes to HCC aggressiveness.
Highlights
As one of the most common cancers with increasing morbidity, hepatocellular carcinoma (HCC) is the sixth most common malignancy and the second most frequent cause of cancer death in the word [1]
To examine a series of Long non-coding RNAs (lncRNAs) related to Hepatitis B virus X protein (HBx) functional processes, we identified genome-wide lncRNA expression in HepG2 HCC cells Ad-HBx– or Ad-N–infected HepG2 HCC cells using microarrays
The results revealed that MSH3 was upregulated by RP11-241J12.3, which had (See figure on page.) Fig. 4 LncRNA RP11-241J12.3 accelerated HCC growth in vivo. a Images of tumors that developed in nude mice. b Tumor growth curves of SMMC-7721 cells transduced with Lv-241J12.3 and Lv-NC in nude mice
Summary
As one of the most common cancers with increasing morbidity, hepatocellular carcinoma (HCC) is the sixth most common malignancy and the second most frequent cause of cancer death in the word [1]. Chronic hepatitis B virus (HBV) infection is the most important risk factor for hepatocarcinogenesis [2]. Recent reports claim that at least 250 million people worldwide are chronically infected with. Hepatitis B virus X protein (HBx) has been verified to act as a multifunctional regulator of HCC through its influence on cell cycle progression, apoptosis, and transcriptional regulation [4,5,6]. Our previous study revealed that HBx induces DNA damage and interferes in glucose, lipid and nucleic acid metabolism [7]. The molecular mechanism of HBx mediated hepatocarcinogenesis remains largely unclear, especially the mechanism by which HBx causes metabolic disturbance and DNA damage
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