A novel tumor suppressor ASMTL-AS1 regulates the miR-1228-3p/SOX17/β-catenin axis in triple-negative breast cancer

• Published in: Diagnostic pathology 2021-05, Vol.16 (1), p.45-9, Article 45
• Main Authors: Sun, Jie, Li, Xiaohua, Yu, Enqiao, Liu, Jianxia, Sun, Liang, He, Qin, Lu, Qiran
• Format: Article
• Language: English
• Subjects: Adult; Animals; ASMTL-AS1; Assaying; beta Catenin - genetics; beta Catenin - metabolism; Binding sites; Breast cancer; Cancer therapies; Carcinogens; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemotherapy; Cloning; Female; Gene expression; Gene Expression Regulation, Neoplastic; Humans; In vivo methods and tests; Inactivation; Localization; Metastasis; Mice; Mice, Nude; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA sponges; Neoplasm Invasiveness; Non-coding RNA; Pathogenesis; Polymerase chain reaction; Prognosis; Proteins; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; SOXF Transcription Factors - genetics; SOXF Transcription Factors - metabolism; Therapeutic targets; TNBC; Transplantation; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor Burden; Tumor cells; Tumor suppressor genes; Tumors; Wnt protein; Wnt Signaling Pathway; Wnt/β-catenin pathway; Xenografts; Xenotransplantation; β-Catenin
• ISSN: 1746-1596; 1746-1596
• DOI: 10.1186/s13000-021-01105-3

Triple-negative breast cancer (TNBC) is a special type of breast cancer that lacks effective therapeutic targets. There is a significant need to clarify its pathogenesis, so as to bring new targeted approaches for TNBC management. Here, we identified a long-non coding RNA (lncRNA) ASMTL-AS1 that linked to TNBC development and progression. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assays were used to test gene and protein levels, respectively. The regulatory axis of miR-1228-3p/SOX17/β-catenin was determined by luciferase reporter and RNA pull-down assays. In vivo assay was conducted by using the nude mice model via subcutaneous transplantation of tumor cells. ASMTL-AS1 was significantly downregulated in TNBC tissues compared to normal tissues, which was closely associated with aggressive clinical features and unfavorable prognosis. Lentivirus-mediated ASMTL-AS1 overexpression evidently reduced the ability of TNBC cell colony formation, activity and invasion by more than 2.5 times. RNA pull-down and luciferase reporter assays revealed that miR-1228-3p directly bound to ASMTL-AS1, ASMTL-AS1 increased SOX17 expression via sponging and repressing miR-1228-3p. Subsequently, the upregulated SOX17 trans-suppressed β-catenin expression, resulting in the inactivation of carcinogenic Wnt/β-catenin signaling, thereby restraining TNBC cell growth and dissemination. Importantly, the xenograft tumor model showed that the ASMTL-AS1 overexpression significantly retarded tumor growth, and negatively regulated Wnt/β-catenin pathway. Our data characterize a novel tumor suppressor in TNBC, restoration of ASMTL-AS1 may be a candidate therapeutic intervention for TNBC patients.