Long noncoding RNA-SRLR elicits intrinsic sorafenib resistance via evoking IL-6/STAT3 axis in renal cell carcinoma

• DOI: 10.1038/onc.2016.356
• Publication Date: 2016-11-14T16:39:24Z
• Authors: Z Xu; F Yang; D Wei; B Liu; C Chen; Y Bao; Z Wu; D Wu; H Tan; J Li; J Wang; J Liu; S Sun; L Qu; L Wang
• Keywords: Niacinamide; STAT3 Transcription Factor; 0303 health sciences; Interleukin-6; Gene Expression Profiling; Phenylurea Compounds; Sorafenib; Microarray Analysis; Kidney Neoplasms; 3. Good health; 03 medical and health sciences; Drug Resistance, Neoplasm; Cell Line, Tumor; Biomarkers, Tumor; Humans; RNA, Long Noncoding; Carcinoma, Renal Cell; Signal Transduction

Although the use of sorafenib appears to increase the survival rate of renal cell carcinoma (RCC) patients, there is also a proportion of patients who exhibit a poor primary response to sorafenib therapy. It is therefore critical to elucidate the mechanisms underlying sorafenib resistance and find representative biomarkers for sorafenib treatment in RCC patients. Herein, we identified a long non-coding RNA referred to as lncRNA-SRLR (sorafenib resistance-associated lncRNA in RCC) that is upregulated in intrinsically sorafenib-resistant RCCs. lncRNA-SRLR knockdown sensitized nonresponsive RCC cells to sorafenib treatment, whereas the overexpression of lncRNA-SRLR conferred sorafenib resistance to responsive RCC cells. Mechanistically, lncRNA-SRLR directly binds to NF-κB and promotes IL-6 transcription, leading to the activation of STAT3 and the development of sorafenib tolerance. A STAT3 inhibitor and IL-6-receptor antagonist both restored the response to sorafenib treatment. Moreover, a clinical investigation demonstrated that high levels of lncRNA-SRLR correlated with poor responses to sorafenib therapy in RCC patients. Collectively, lncRNA-SRLR may serve as not only a predictive biomarker for inherent sorafenib resistance but also as a therapeutic target to enhance responses to sorafenib in RCC patients.