LINK-A Functions As A Novel CeRNA To Promote Growth And Metastasis In Hepatocellular Carcinoma Via Regulating RAP2A Expression

As the tumor with the forth incidence and the third cancer-associated mortality in China,hepatocellular carcinoma(HCC)is threatening public health due to its high intratumoral heterogeneity,large probability of relapse and metastasis after surgical resection with increasing morbidity and mortality.However,the mechanisms underlying HCC carcinogenesis and progression are far beyond our grasp,which need to be deeply investigated,to improve clinical early-stage diagnosis and prediction on the prognosis of HCC patients.LncRNAs(long non-coding RNAs),the crucial part of non-coding RNA,are highlighted by mounting researchers due to its roles for regulation mechanisms in various pathology and physiology processes.Previous studies have suggested that lncRNAs are able to regulate expression of coding gene in different periods and manners,including gene transcription and posttranscriptional levels.Besides,many lncRNAs have been recognized as potential biomarkers for the prediction on the diagnosis and prognosis of numerous diseases.There are accumulating evidence that lncRNAs have the ability to compete with mRNAs for miRNA(microRNA),sequestering mRNA from the translation inhibition by miRNA.The mechanism is called competitive endogenous RNA(ceRNA)network.RAP2A,a member of Ras superfamily,which was reported to accelerate migration and invasion of renal cell carcinoma,osteosarcoma and non-small-cell lung cancer cell and so on.However,the roles of RAP2 A in HCC are not investigated and the mechanism regulating RAP2 A remains to be clarified.In our study,LINK-A was found upregulated in HCC,and elevated LINK-A expression in HCC tumor tissues is related to poor pathological characteristics and prognosis.Overexpression and knockdown experiments suggested that HCC cell proliferation was promoted by LINK-A,as well as migration and invasion.In addition,LINK-A downregulation arrested cell cycle and increased apoptosis.LINK-A was verified to enhance the growth and metastasis of HCC via in vivo experiments.Mechanism analysis suggested that LINK-A reinforced PI3K/AKT/mTOR pathway by functioning as a novel competing endogenous RNA to liberate RAP2 A expression from miR-545-5p.