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

Oncogene volume 36, pages 1965–1977 (2017)Cite this article

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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.

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Accession codes

Accessions

Gene Expression Omnibus

Abbreviations

RCC:

renal cell carcinoma

STAT3:

Signal transducer and activator of transcription 3

NF-κB:

nuclear factor kappa-light-chain-enhancer of activated B cells

IL-6:

interleukin-6

KIT:

stem-cell growth factor receptor

Bcl-2:

B-cell CLL/lymphoma 2

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Acknowledgements

We thank Dr Feng Liu and Qifei Tao for editing this manuscript. This study was supported by grants from the National Natural Science Foundation of China (81272817, 81472691 and 81572521), the Leading Talent Project of Shanghai (2013046) and Youth Talent Sailing Program of Shanghai Science and Technology Committee (16YF1403600).

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  1. Z Xu, F Yang and D Wei: Co-first author.

Authors and Affiliations

  1. Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China

    Z Xu, B Liu, Y Bao, Z Wu, D Wu, H Tan, J Li, J Wang, J Liu, L Qu & L Wang

  2. Department of Medical Genetics, Second Military Medical University, Shanghai, China

    F Yang & S Sun

  3. Division of Endocrinology, Department of Internal Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China

    D Wei

  4. Department of Medical Oncology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing, China

    C Chen

  5. Department of Urology, Jinling Hospital, Nanjing University Clinical School of Medicine, Nanjing, China

    L Qu

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Correspondence to S Sun, L Qu or L Wang.

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Xu, Z., Yang, F., Wei, D. et al. Long noncoding RNA-SRLR elicits intrinsic sorafenib resistance via evoking IL-6/STAT3 axis in renal cell carcinoma. Oncogene 36, 1965–1977 (2017). https://doi.org/10.1038/onc.2016.356

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