Severe　acute　respiratory　syndrome　coronavirus　2　(SARS-CoV-2)　has　becoming　globally　public　health　threat.　Recently　studies　were　focus　on　SARS-CoV-2　RNA　to　design　vaccine　and　drugs.　It　was　demonstrated　that　virus　RNA　could　play　as　sponge　to　host　noncoding　RNAs　to　regulate　cellular　processes.　Bioinformatic　research　predicted　a　series　of　motif　on　SARS-CoV-2　genome　where　are　targets　of　human　miRNAs.　In　this　study,　we　used　dual-luciferase　reporter　assays　to　validate　the　interaction　between　3’UTR　of　SARS-CoV-2　S　(S-3’UTR)　gene　and　bioinformatic　predicted　targeting　miRNAs.　The　growth　of　293T　cells　and　HUVECs　with　overexpressed　S-3’UTR　was　determined,　while　miRNAs　and　IL6,　TNF-α　levels　were　checked　in　this　condition.　Then,　miR-296　and　miR-602　mimic　were　introduced　into　293T　cells　and　HUVECs　with　overexpressed　S-3’UTR,　respectively,　to　reveal　the　underlying　regulation　mechanism.　In　results,　we　screened　19　miRNAs　targeting　the　S-3’UTR,　including　miR-296　and　miR-602.　In　293T　cell,　S-3’UTR　could　inhibit　293T　cell　growth　through　down-regulation　of　miR-296.　By　reducing　miR-602,　S-3’UTR　could　induce　HUVECs　cell　proliferation,　alter　the　cell　cycle,　reduce　apoptosis,　and　enhanced　IL6　and　TNF-αlevel.　In　conclusion,　SARS-CoV-2　RNA　could　play　as　sponge　of　host　miRNA　to　disturb　cell　growth　and　cytokine　signaling.　It　suggests　an　important　clue　for　designing　COVID-19　drug　and　vaccine.　Copyright　©　2022　Yuan,　Feng,　Wang,　Han,　Guan,　Liu,　Ye,　Xu　and　Han.