LINC00160 Mediates Sunitinib Resistance via SAA1/STAT3 Signaling Pathways and ABCB1 Transmembrane Transport in Renal Cell Carcinoma

Patients with advanced renal cell carcinoma (RCC) who are resistant to sunitinib currently have limited clinical options for treatment. Therefore, it is necessary to explore the biological basis of sunitinib resistance and to uncover new targets for the intervention of sunitinib resistance. In this study, we identified that long non-coding RNA 160 (LINC00160) was associated with sunitinib resistance in RCC. Resistant RCC cells highly expressed LINC00160 to recruit transcriptional factor AP-2 alpha (TFAP2A), which bound to serum amyloid A1 (SAA1) promoter regions and activated its expression. On one hand, SAA1 linked to ATP binding cassette subfamily B member 1 (ABCB1) protein, which facilitated sunitinib cellular efflux and diminished drug accumulation. On the other hand, SAA1 stimulated JAK-STAT signaling pathways, which countered cellular survival inhibition from drug. All these regulatory networks were well organized and collaborated, thus promoting sunitinib resistance in renal cell carcinoma. LINC00160 mediates sunitinib resistance via SAA1/STAT3 signaling pathways and ABCB1 transmembrane transport in RCC, which offers an opportunity for targeted intervention and molecular therapies in the future. Funding Statement: Our study was supported by the Key Research and Development Plan in China (Grant No. 2017YFB1303100), the National Natural Science Foundation of China (Grant No. 81927807, 81874090, 81672528, 81773282 & 81972630) and Individual Innovative Research Funding of Union Hospital (Grant No. 02.03.2019-156). Declaration of Interests: The authors declared no conflicts of interest. Ethics Approval Statement: This study was approved by the Ethics Committees of Huazhong University of Science and Technology, and all aspects of the study comply with the criteria established by the Declaration of Helsinki. Animal experiments were approved by the Institutional Animal Use and Care Committee of Tongji Medical College, Huazhong University of Science and Technology (HUST).