Predictive Value Of Long Non-coding RNA MALAT-1in Tumor Recurrence Of Patients With Hepatocellular Carcinoma After Liver Transplantation

Background:Long noncoding RNAs (lncRNAs) are considered to be the transcripts longer than200nucleotides. Although distinguishing lncRNAs from other protein-coding mRNAs that lack open reading frames, they have showed to play pivotal roles in modulating the cancer epigenome, transcriptional regulation and Post-transcriptional regulation thus regulating gene expression. Recent studies found that lncRNAs had been previously overlooked, many long ncRNAs with a known function in tumor progress. In-depth study of lncRNA would arouse revolutionary changes in cancer research. The nuclear-retained long non-coding RNA MALAT1was identified to have overexpression in many human carcinomas, including those of the lung, breast, colon, pancreas, prostate, and liver, and was associated with the metastatic potential of some cancers. The role of MALAT-1in hepatocellular carcinoma was remained elusive, and needed to be illustrated.Objective:To investigate the expression of lncRNA MALAT-1in HCC and evaluated the association of MALAT-1overexpression with the prognosis of patients with HCC ater liver transplantation. Moreover, its significance in biological functions in HCC progression was also investigated.Methods:In the present study, we evaluated the expression of MALAT1by quantitative real-time PCR in11liver cancer cell lines and112HCC cases including60cases who received liver transplantation (LT) with complete follow up data, and the clinicopathological significance of the MALAT-1expression was evaluated. Moreover, small interfering RNA (siRNA) was used to inhibit MALAT1expression to investigate its biological role in tumor progression, such as tumor proliferation; apoptosis; cell mobility and invasiveness.Results:We found that MALAT-1was up-regulated in liver cancer cell lines and clinical samples, its overexpression was detected in73.1%(38/52) HCC patients. Expression level of MALAT1had no clinicopathological significance with age, sex, tumor size, portal vein tumor thrombi and histological grade, but it was correlated with preoperational AFP level(P=0.03), tumor number (P=0.028)and tumor recurrence (P=0.048). LncRNA MALAT-1was expressed at high levels in most reccurece patients (65.7%), by contrast, in recurrence-free patients, MALAT-1up-regutaion was20%. Moreover, the3-year disease-free survival rate was55.6%in the MALAT-1-low group, whereas it was only30.3%in MALAT-1-high group (P=0.01). On multivariate analysis, patients with high expression level of MALAT1had a significantly increased risk of tumor recurrence after LT (hazard ratio,3.280,95%CI:1.156-7.094, P=0.003), particularly in patients who exceeded the Milan criteria. Subsequent functional studies showed that inhibition of MALAT1in HepG2cells by siRNA could effectively reduce cell viability, motility, invasiveness, and increase the sensitivity to apoptosis by most biochemical stimulus, such as Cisplatin (CDDP), doxorubicin(DOX), staurosporine(STS), and tumor necrosis factor-a (TNF-a). Conclusion:Up-regulation of lnc RNA MALAT1was a frequent event in human HCC and play a pivotal role in cell proliferation; apoptosis; cell mobility and invasiveness. Overexpression of MALAT-1could be a potential prognostic factor for patients with HCC after LT and serve as a promising therapeutic target.