| Hepatocellular carcinoma (HCC) is one of the most common human cancer worldwide, particularly in Southeast Asia and Africa. Unfortunately, the 5-year survival rate of HCC patient remains poor and ~600 000 HCC patients die each year despite recent advances in surgical techniques and medical treatment. Although previous studies identified many aberrantly expressed protein-coding genes in HCC, the novel molecular markers that can help to early diagnosis and risk assessment are still urgently needed. It is also paramount important to understand the relationships between clinical symptoms and molecular changes in HCC for developing new diagnosis and treatment of HCC and improving the prognosis of diagnosed patients.In this study, we used hybridization-based microarrays and two-dimensional electrophoresis proteomic approach to investigate the roles of protein, miRNAs and long non-coding RNAs (lncRNAs) in HCC. Our research has achieved the following results:First, we found some novel prognostic biomarkers of chronic hepatitis B (CHB) or HCC in this study. In recent years, identifying the molecular markers correlating with the survival of cancer patients attracts much attention. For HCC, deregulated expression of both protein-coding genes and miRNAs has been suggested to have considerable potential in predicting the prognosis of HCC patients. Using a microarray platform, we identified a long non-coding RNA (termed lncRNA-HEIH), a novel mRNA-like noncoding RNA, as one of the up-regulated genes in HCC. We found that patients with lncRNA-HEIH high expression tumors had an increasing risk of recurrence and significantly reduced overall postoperative survival. Furthermore, univariate and multivariate analyses revealed that lncRNA-HEIH expression was a powerful independent prognostic factor for both recurrence and survival of HCC patients, which is consistent with the results from cell culture and with the notion that lncRNA-HEIH expression may be used as a novel prognostic biomarker of HCC. Apo A-I expression is down-regulated in male and female HBV-transgenic (HBV-Tg) mouse liver and that there is a disordered expression pattern of Apo A-I isoforms in male HBV-Tg mouse liver. We also verified this finding in CHB patient serum. Furthermore, we identified overoxidized Apo A-I mainly resides in basic isoform (isoform 3). Although it is not clear at present whether the occurrence of these modifications has a causal role or simply reflects secondary epiphenomena, the selectively modified Apo A-I isoforms may be considered to be a pathological hallmark that could extend our knowledge of the molecular pathogenesis of CHB. Development of antibodies that specifically recognize the isoforms of Apo A-I may prove to be useful, in combination with other traditional markers, as a more efficient way to evaluate the prognosis of CHB.Second, our study increased understanding the relationships between clinical symptoms and molecular changes in HCC. Our findings suggest that the p38 MAPK pathway plays a crucial role in miR-17-5p-induced phosphorylation of heat shock protein 27 (HSP27) and, as a consequence, phosphorylated HSP27 enhances the migration of HCC cells. Our data highlight an important role of miR-17-5p in the proliferation and migration of HCC cells and support the potential application of miR-17-5p in HCC therapy. We also identified non-overlapping signatures of a small number of lncRNAs that are aberrantly expressed in human HCC compared with paired peritumoral tissues. Then we used real-time PCR to validate five lncRNAs whose expression was altered in HCC compared with paired peritumoral tissues. Using loss-of-function and gain-of-function approaches, we found that lncRNA-HEIH plays a key role in cell cycle regulation. We further demonstrated that lncRNA-HEIH bound to enhancer of zeste homolog 2 (EZH2) and that this interaction was required for the repression of EZH2 target genes. These results reveal insights into the molecular regulation mechanisms of HCC cell cycle regulation and lead us to propose that lncRNAs may serve as key regulatory hubs in cancer biology. The present study also provides new insights into the pathogenesis of hepatitis B virus infection, which might not be obtained by studying a specific individual molecule. In addition to a close connection between glutathione peroxidase 1and oxidative stress, our integrated approach highlighted the fact that fatty acid binding 5, Acyl-CoA binding protein and apo A-I could be the key points of lipid metabolism derangement in HBV-Tg mice. Our study also shed light on the physiological difference between HBV-Tg and wild-type mice, which may pave the way for further use of HBV-Tg mice for the study of pathogenesis of hepatitis B virus infection.Overall, our finds have diagnostic and therapeutic implications. Understanding the precise molecular mechanisms in HCC will be critical for exploring these potential new strategies for early diagnosis and therapy of HCC.
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