title: Long noncoding RNA-SRLR elicits intrinsic sorafenib resistance via evoking IL-6/STAT3 axis in renal cell carcinoma.
abstract: 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.
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Medical Genetics, Second Military Medical University, Shanghai, China.
authors.forename: F
authors.initials: F
authors.lastname: Yang
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: D
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing, China.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Tan
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medical Genetics, Second Military Medical University, Shanghai, China.
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.|Department of Urology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Qu
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D046228:Microarray Analysis; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D062085:RNA, Long Noncoding / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077157:Sorafenib
chemical_list: D014408:Biomarkers, Tumor; D015850:Interleukin-6; D010671:Phenylurea Compounds; D062085:RNA, Long Noncoding; D050796:STAT3 Transcription Factor; D009536:Niacinamide; D000077157:Sorafenib