The Role And Clinical Significance Of Long Noncoding RNA In Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of most common solid tumors worldwide,with the incidence on the rise. About one half of new cases are occurred in China andlead to the second tumor-related deaths ranking after lung cancer. Sustainedinflammation activated by the hepatitis virus infection are responsible for the majorityof HCC in China. Hepatocarcinogenesis is a stepwise process evolving from normalthrough chronic hepatitis, cirrhosis and dysplastic nodule to hepatocellular carcinoma.Although great progress have achieved for curative hepatectomy and adjuvanttherapies like TACE in the past decades, the survival of HCC patients remainsunsatisfied, mainly attributing to fact that low rate of patients could be applied forcurative therapy and frequent recurrence after resection. Even for curative therapy, themedian survival rate remains at approximately50%(17-69%) for5years. Recentworks have sought to uncover the mechanisms underlying the initiation, propagationand development, which would supply opportunities to seek candidate diagnosticbiomarkers and therapeutic targets.Long non-coding RNA (lncRNA) represent a subgroup of non-coding RNA thatare longer than200nucleotides. For a long time, the gene locus of lncRNAs weresupposed to be “noises” of genome. Recently, studies have shown that more genomicsequence is transcribed into lncRNAs than protein-coding RNAs. Additionally,multiple studies have indicated that numbers of lncRNAs are involved and might playcentral roles in a variety of biological processes through complicated mechanisms.Notably, the deregulation of lncRNAs has also been shown to result in aberrant geneexpression that contributes to the progression of a variety of human tumors includingHCC. However, compared with protein-coding genes, the expression profiles oflncRNAs and the role of most lncRNAs in the progression and aggressiveness ofHCC remain unknown.Part1. The expression profiling and analysis of lncRNAs innormal, chronic hepatitis, cirrhotic and HCCThe expression profiles and potential role of long noncoding RNAs indevelopment and progression of HCC remains largely unknown. In the present study,we globally measured expression profiles of lncRNAs and mRNAs in liver samplesrepresenting the multiple stages of hepatic dysfunction from hepatitis/cirrhosis toearly and advanced HCC. We found that aberrant expression of lncRNAs when compared HCC with corresponding paratumoral tissues and comparedmetastasis-inclined HCC and metastasis-against HCC. Remarkably, we noticed alncRNA-MVIH was significantly up-regulated in HCC tissues frommetastasis-inclined HCC, suggesting the potential role of MVIH in metastasis. Weidentified disease-related gene groups including abundant lncRNAs and refined atransformation gene signature which might recapitulate the progression of cancerousformation. Amongst, we found that lncRNA-DANCR might be essential fortumorigenesis activated by inflammation. Moreover, we noticed that combination oflncRNAs with mRNAs would be more accurate to predict the metastatic potential ofHCC. In conclusion, we systematically explored the expression profiles and theclinical significance of lncRNAs in development and progression of HCC. Moreover,we focus on MVIH and DANCR for further researches by bioinformatics analysis.Part2. Long noncoding RNA-MVIH promotes angiogenesisand serves as a predictor for hepatocellular carcinoma patients’poor recurrence-free survival after hepatectomyThe unfavorable prognosis of HCC is mainly because HCC is a highlyvascularized type of tumor with frequent intrahepatic or extrahepatic metastases. Theblood vessels within the tumors produced by angiogenesis are responsible for the poorsurvival of HCC patients. However, the mechanisms underlying angiogenesis in HCCremain to be discovered. In this study, we found that long noncoding RNA MVIH(lncRNA associated with microvascular invasion in HCC) was generallyoverexpressed in HCC. In a cohort of215HCC patients, the overexpression of MVIHwas associated with frequent microvascular invasion (P=0.016) and a higher tumornode metastasis stage (P=0.009) as well as decreased recurrence-free survival (RFS)(P <0.001) and overall survival (P=0.007). Moreover, the up-regulation of MVIHserved as an independent risk factor to predict poor RFS. We also found that MVIHcould promote tumor growth and intrahepatic metastasis by activating angiogenesis inmouse models. Subsequent investigations indicated that MVIH could activatetumor-inducing angiogenesis by inhibiting the secretion of phosphoglycerate kinase1(PGK1). Additionally, in65HCC samples, MVIH expression was inverselycorrelated with the serum level of PGK1and positively correlated with themicrovessel density. Conclusion: Deregulation of lncRNA MVIH is a predictor forpoor RFS of HCC patients after hepatectomy and could be utilized as a potential target for new adjuvant therapies against active angiogenesis.Part3. Long noncoding RNA DANCR expandstumor-intiatiating cells of hepatocellular carcinoma viade-repression of CTNNB1.Sustained hepatic inflammation contributes to cancer initiation and progressionvia tumor-initiating cell expansion, but underlying mechanisms remains unknown.We found a conserved lncRNA DANCR, which is silenced in normal livers, butoverexpressed in fetal and cancerous livers, is an independent for prognosis of HCCpatients. DANCR, directly regulated by NF-κB and p-STAT3, could suppress celldifferentiation and drive expansion of tumor-initiating cells. In vitro and in vivoinhibition confirms the significance of DANCR as a therapeutic target. Furthermore,we illustrate the role of DANCR relies on the regulation of CTNNB1in a novelmiRNA-blocking manner. Our studies reveal the expression of lncRNAs/mRNAs innormal and pathological livers and suggest the importance of oncofetal lncRNADANCR in inflammation-induced malignant transformation, offering a potentialprognostic marker and therapeutic target for HCC.