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.

<p>LncRNA DANCR Promotes Sorafenib Resistance via Activation of IL-6/STAT3 Signaling in Hepatocellular Carcinoma Cells</p>

“…Among them, IL-6/STAT3 signaling pathway is capable to modulate a series of genes expressions to enhance tumor growth, metastasis, inflammation, angiogenesis as well as sorafenib resistance. 31,35,36 Recently, several lncRNAs have been found to have an impact on the STAT3 activation. For instance, IL-6 expression is regulated by lncRNA-DILC and lncRNA-SRLR.…”

“…For instance, IL-6 expression is regulated by lncRNA-DILC and lncRNA-SRLR. 31,37 LncRNA lncSox4 recruits STAT3 to form complex to activate Sox4 transcription and facilitate the self-renewal of liver tumor-initiating cells. 38 Moreover, lncRNA PVT1 increases the phosphorylation level of STAT3 protein to induce angiogenesis.…”

“…Sustaining activation of IL-6/STAT3 signaling is crucial for sorafenib resistance. [29][30][31] Recent studies reported that PSMD10 could active IL-6/STAT3 signaling by facilitating the phosphorylation of Rb and IL-6 transcription, thereby promoting sorafenib resistance. 10,32 Based on these studies, we speculated that DANCR may have an effect on IL-6/STAT3 signaling via PSMD10.…”

The Network of Non-coding RNAs in Cancer Drug Resistance

“…Moreover, knock-down of TUC338 lncRNA increased expression of RASAL1 protein in HCC, inhibited tumor growth and sensitized cells to sorafenib (328). Sorafenib is also used in the treatment of renal carcinoma (RCC), where SRLR (sorafenib resistance-associated lncRNA in RCC) was found up-regulated in sorafenib-resistant RCCs and contributed to sorafenib tolerance (329). …”

Down‐regulation of PKM2 enhances anticancer efficiency of THP on bladder cancer

“…This indicates that STAT3 plays an important role in the pharmacodynamics of THP. STAT3 is a member of the STAT family of transcription factors and is activated in several cancers including osteosarcoma,8 renal cell carcinoma,9 and pancreatic cancer 10. Inhibition of STAT3 could serve as a potent chemotherapeutic sensitizing strategy to overcome drug resistance in chemoresistant cancer cells 11, 12.…”