The Biological Function of TUSC7/miR-1224-3p Axis in Triple-Negative Breast Cancer

Bo-Hao Zheng,1,2,* Zhi-Xian He,3,* Juan Zhang,4,* Jing-Jing Ma,5,* Hong-Wei Zhang,1,2 Wei Zhu,1,2 Zhi-Min Shao,6 Xiao-Jian Ni1,2 1Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, People’s Republic of China; 4Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, 200032, People’s Republic of China; 5State Key Laboratory of Reproductive Medicine, Department of Breast Surgery, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, 210004, People’s Republic of China; 6Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Cancer Center and Cancer Institute, Fudan University, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Jian NiDepartment of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of ChinaTel/Fax +86-21-64041990Email ni.xiaojian@zs-hospital.sh.cnZhi-Min ShaoDepartment of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Cancer Center and Cancer Institute, Fudan University, Shanghai, 200032, People’s Republic of ChinaTel/Fax +86-21-64175590Email shaozhimingfd@163.comBackground: Triple-negative breast cancers (TNBC), comprising about 20% of breast cancers, have a poor prognosis. Currently, there is no effective target therapy for TNBC. LncRNA TUSC7 has been identified as a tumor suppressor in osteosarcoma and colorectal cancer. In this study, we investigated the clinical significance and the biological function of TUSC7 in breast cancer.Methods: We retrospectively evaluated the expression level and clinical significance of TUSC7 in 90 paired breast cancer tissues and normal tissues. The proliferation, migration, and invasion assays were performed to investigate the biological function of TUSC7 in breast cancer. Finally, microarray, a luciferase reporter assay, and quantitative real-time polymerase chain reaction (qPCR) were used to explore the potential underlying mechanism of tumor suppressor role of TUSC7.Results: Low TUSC7 expression was found to be an independent prognostic factor of poor overall survival (OS) in TNBC patients. Ectopic expression of TUSC7 inhibited tumor cell growth both in vitro and in vivo. TUSC7 overexpression significantly promoted the sensitivity of MDA-MB-468 cells to paclitaxel and carboplatin. In terms of the mechanism, TUSC7 might perform its biological function through binding with miR-1224-3P and regulating its expression level. Besides, genes in cell cycle pathways, such as BUB3 (budding uninhibited by benzimidazoles 3) and TGF-ß (targeting transforming growth factor β) pathways were downregulated, and genes involved in the MAPK (mitogen-activated protein kinase) (TGFBR2, transforming growth factor-beta receptor 2), PI3K-AKT (phosphoinositide 3-kinase- AKT serine/threonine kinase 1) and NF-κB (nuclear factor-kappa B subunit) pathways were upregulated in TUSC7 knockdown MDA-MB-231 cells.Conclusion: The low TUSC7 expression is an independent prognostic factor of poor OS of TNBC patients. TUSC7 might inhibit breast cancer cell growth and metastasis both in vitro and vivo through binding with miR-1224-3P and regulating MAPK, PI3K/AKT, and NF-κB signaling pathways.Keywords: TUSC7, long non-coding RNA, MiR-1224-3P, triple-negative breast cancer, prognosi