Investigation Of Long Noncoding RNA-SRLR Contributing To Sorafenib Resistance In Renal Cell Carcinoma

Background and Objective The introduction of sorafenib apparently improved the prognostic of renal cell carcinoma(RCC)patients.However,approximately 20%RCC patients presented nonresponsive to sorafenib initially.The primary resistance of sorafenib remains largely unknown and no representative biomarker are available sorafenib benefits.lncRNA has been found of great significance in various biological processes,and recent study found that lncRNA also exerted significant role in drug resistance and might be biomarkers for drug response.However,the association between sorafenib-resistance and lncRNA has been rarely reprtred.Our study aimed to explore the mechanism underlying the sorafenib-resistance and find valuable molecular for sorafenib benefits in RCC patients.Methods 1)RNA Microarray analysis was assayed to select differential lncRNA between sorafenib responsive and nonresponsive RCC tissues.2)Another cohort sorafenib treated RCC patients were used for further identify representative lncRNA.8kinds of RCC cell lines were conducted to test the sorafenib IC50 and divided to responsive and nonresponsive groups for further identify the lncRNA.3)Knockdown or overexpressed lncRNA-SRLR RCC cells were assayed to detect their sorafenib response.4)Exnograft the overexpressed and control RCC cells into nude mices and treated with sorafenib,compared the tumor growth between these two groups.5)Exploring the downstream of lncRNA by screening potential pathways of RTKs.And rescue assays to confirm its importance in sorafenib responseness.6)Identifying the association between prognosic and sorafenib treated RCC patients.Results The expression of lncRNA-SRLR(sorafenib resistance associated lncRNA in renal cell carcinoma)was of high level in intrinsic sorafenib-resistant RCCs.lncRNA-SRLR knockdown sensitized nonresponsive-RCC cells to sorafenib treatment,whereas overexpression of lncRNA-SRLR conferred sorafenib resistant to responsive-RCC cells.Mechanistically,lncRNA-SRLR directly bound to NF-?B and promoted IL-6 transcription,leading to the activation of STAT3.STAT3 inhibitor or IL-6-receptor antagonist restored the response to sorafenib treatment.Moreover,clinical investigation demonstrated that the high levels of lncRNA-SRLR correlated with poor response to sorafenib therapy in RCC patients.Conclusions lncRNA-SRLR mediates the intrinsic sorafenib-resistance via NF-?B/IL-6/STAT3 axis.lncRNA-SRLR may serve as not only a predictive biomarker for inherent sorafenib resistance,but also as a therapeutic target to enhance sorafenib response in RCC patients.