The Function And Mechanism Of IFN-induced LncRNA IRF1-AS In Esophageal Squamous Cell Carcinoma

Esophageal cancer is one of the most common cancers in China,and patients in China accounts for nearly 50%of all the patients around the world.In China,more than 90%of the esophageal cancer patients are squamous cell carcinoma,which is different from the dominance of adenocarcinoma in western countries.Up to now,surgery resection is the most effective treatment of esophageal squamous cell carcinoma(ESCC).However,due to high rates of postoperative recurrence and metastasis and insensitivity to chemoradiotherapy,the total five-year survival rate is just around 15%-25%.The deeper illustration of mechanisms in the initiation and progression of ESCC is vital important for the early stage diagnosis,effective treatment and improving patients' outcome.Interferons(IFNs)are pleiotropic cytokines that have been considered to be involved in the development and treatment of cancer.Interferons play crucial antitumor roles via their direct inhibitory effects on cancer cells and activation of antitumor immune responses.Researchers tried a lot to exploit interferon pathway therapeutically,which achieved unsatisfactory clinical application due to the unpredictable therapeutic effects on cancer patients and toxic side effects.Long non-coding RNAs(lncRNAs)play important roles in cancer initiation and progression by affecting cancer cell proliferation,apoptosis,metastasis,metabolism and drug resistance.Many lncRNAs are dysregulated in ESCC,which are vital important for ESCC progression.Interferons and lncRNAs both paly crucial roles in the development of ESCC.However,the crosstalk between interferon pathway and lncRNAs in the development of ESCC are largely unknown.Therefore,illustration the interferon regulated lncRNAs and their roles in the development of ESCC is vital important for deeper understanding the mechanisms of ESCC development,and exploiting novel targets for diagnosis and treatment.In our study,we identified and characterized an IFN-inducible nuclear lncRNA IRF1-AS(Interferon Regulatory Factor 1 Antisense RNA)which was positively correlated with IRF1 expression.IFNs upregulate IRF1-AS via the JAK-STAT pathway.Knockdown and overexpression of IRF1-AS revealed that IRF1-AS inhibits esophageal squamous cell carcinoma(ESCC)proliferation and promotes ESCC apoptosis in vitro and in vivo.Mechanistically,IRF1-AS activates IRF1(Interferon Regulatory Factor ?)transcription through interacting with ILF3(Interleukin Enhancer Binding Factor 3)and DHX9(DEx-HBox Helicase 9).In turn,IRF1 binds to the IRF1-AS promoter directly and activates IRF1-AS transcription.Global analysis of IRF1-AS—regulated genes indicated that IRF1-AS activates the IFN response in vitro and in vivo.IRF1 knockdown in IRF1-AS-overexpressing cells abolished the antiproliferative effect and activation of the IFN response.Furthermore,IRF1-AS was downregulated in ESCC tissues,and low expression correlated with poor prognosis.In conclusion,our results indicate that IFN-induced IRF1-AS is a tumor suppressive lncRNA that enhances interferon response through a positive regulatory feedback loop with IRF1 in ESCC.The regulatory network among IFN response,IRF1-AS and IRF1 provides novel insights into deeper understanding the mechanisms of ESCC development,and exploiting new targets for ESCC diagnosis and treatment.