The Regulatory Roles Of LncRNA MALAT1 In Hepatocellular Carcinoma As Revealed By Multiomic Analysis

Objective: The appearance of metastatic foci is the leading cause of cancer death,and more than 90% of cancer-related deaths are caused by metastatic disease.Metabolic reprogramming is essential for cancer cells to shed from the primary tumor,overcome nutrition and energy deficiency,and ultimately survive and form metastatic tumors.However,the role of lipid metabolism in malignant tumor metastasis is unclear.In this study,we aimed to study the regulatory effect of long non-coding RNA(lnc RNA)metastasis-associated lung adenocarcinoma transcript 1(MALAT1)on lipid metabolism in hepatocellular carcinoma(HCC)and proposed a new mechanism for MALAT1 regulating HCC cell metastasis.Methods: 1 Transcriptomics data of HCC were downloaded from The Cancer Genome Atla(TCGA)database,and R 3.6.1 was used to analyze the expression of MALAT1 in HCC and normal tissues.The expression of MALAT1 in seven liver cancer cell lines was examined by quantitative real-time polymerase chain reaction(q RT-PCR).2 The differential protein expression in liver cancer cells induced by MALAT1 knockdown was analyzed by quantitative proteomics,and the abudance changes of m RNAs were studied by the RNA sequencing technology.3 Theproteome and transcriptome data were validated by western blotting and q RTPCR.The abudance of unsaturated fatty acid in liver cancer cells was examined by an unsaturated fatty acid detection kit.4 The molecular mechanism by which MALAT1 regulates cellular lipid metabolism through differential alternative splicing it was investigated by q RT-PCR.5 The role of MALAT1 in cell migration was explored by cellular assays and fluorescence photobleaching recovery experiments.Results: 1 The expression level of MALAT1 in liver cancer tissues is relatively higher compared with the corresponding normal tissues(fold change = 2.85,P < 0.001).The expression of MALAT1 gradually elevated with the increasing metastatic potential of liver cancer cell lines,and the abundance of MALAT1 was the highest in LM3 cells.2 Transcriptomic analysis identified 19312 genes.A total of 2662 differentially expressed genes(DEGs)were detected(P < 0.01,fold change > 1.5),of which 1195 were up-regulated and 1467 were down-regulated.Proteomic analysis quantified 6937 protein.A total of 1149 differentially expressed proteins(DEPs)were detected(P < 0.05,fold change > 1.5),of which 664 were up-regulated and 485 were down-regulated.3 MALAT1 down-regulation inhibited the expression of lipid metabolism-related genes,including sterol regulatory element binding transcription factor(SREBF1),stearoyl-Co A desaturase(SCD)and fatty acid desaturase 1(FADS1)(P <0.01).In addition,compared with control cells,MALAT1 knockdown reduced the abudance of cellular unsaturated fatty acids and impaired the fluidity of cell membrane.4 MALAT1 regulates lipid metabolism of HCC cells through regulating differential alternative splicing of pre-SREBF1.5 As the metabolic product of SCD,oleic acid can partially restore the inhibitory effect of MALAT1 down-regulation on tumor cell migration.Conclusion: We explored the role of lnc RNA MALAT1 in HCC by integrated proteomics and transcriptomics analysis,and proposed a new mechanism by which MALAT1 regulated the migration and invasion of liver cancer cells.Our results indicate that downregulation of MALAT1 can reduce the abundance of unsaturated fatty acids by inhibiting the expression of lipid-metabolism-related genes.Functional and mechanistic studies show that MALAT1 regulates the lipid metabolism of HCC cells by regulating the alternative splicing of pre-SREBF1,thereby regulating the migration and invasion capabilities of HCC cells.