Interactions Between lncRNA TUG1 and miR-9-5p Modulate the Resistance of Breast Cancer Cells to Doxorubicin by Regulating eIF5A2

Shuqian Wang,1,* Mengjing Cheng,2,* Xiaoxiao Zheng,2,* Li Zheng,2 Hao Liu,2 Jianju Lu,3 Yu Liu,1 Wei Chen2 1Department of Breast Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, People’s Republic of China; 2Cancer Institute of Integrated Traditional Chinese and Western Medicine, Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, People’s Republic of China; 3Department of Breast Surgery, The First Hospital of Jiaxing, Affiliated Hospital of Jiaxing College, Jiaxing 314000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu LiuDepartment of Breast Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang 310006, People’s Republic of ChinaTel +8613516805637Email liuyu781220@sina.comWei ChenCancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, 234 Gucui Road, Hangzhou, Zhejiang 310012, ChinaTel +8618668097597Email wei_chen@zju.edu.cnPurpose: Breast cancer (BC) is one of the leading causes of cancer-related deaths. Chemoresistance of BC remains a major unmet clinical obstacle. TUG1 (taurine-upregulated gene 1), a long noncoding RNA (lncRNA), and microRNAs (miRNA) are implicated in therapeutic resistance. However, the interactions between TUG1 and miRNAs that regulate doxorubicin (Dox) resistance in BC remain elusive.Materials and Methods: Expression of TUG1 and miR-9 was measured by real-time PCR. EIF5A2 (eukaryotic translation initiation factor 5A-2) was detected by Western blot. Transfection of siRNAs or miRNA inhibitors was applied to silence lncRNA TUG1, eIF5A2 or miR-9. Cell viability, proliferation, and apoptosis were determined by CCK-8 (cell counting kit-8), flow cytometry, and EdU (5-ethynyl-2ʹ-deoxyuridine) assays, respectively. The regulatory relationship between TUG1 and miR-9 was determined by a luciferase assay.Results: LncRNA TUG1 was highly expressed in BC tissues and positively associated with Dox resistance in BC cell lines. SiRNA knockdown of TUG1 reversed Dox resistance in MCF-7/ADR cells. Mechanistically, TUG1 acted as a “sponge” for miR-9 and downregulated miR-9. Treatment with a miR-9 inhibitor blocked the effect of TUG1 siRNA, and knockdown of TUG1 inhibited the effects of miR-9. Furthermore, TUG1 inhibition of apoptosis induced by Dox involved miR-9 targeting of eIF5A2.Conclusion: TUG1 modulates the susceptibility of BC cells to Dox by regulating the expression of eIF5A2 via interacting with miR-9. These results indicate that the lncRNA TUG1 may be a novel therapeutic target in breast cancer.Keywords: TUG1, microRNA-9-5p, breast cancer, doxorubicin resistance, eIF5A2