Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Cell Death Dis. 2022 Sep 19;13(9):800. doi: 10.1038/s41419-022-05189-7.
Long noncoding RNAs (lncRNAs) play crucial regulatory roles in the progression of various cancers. However, the functional roles of lncRNAs in breast cancer remain unclear. In this study, we investigated the functional role of a novel long noncoding RNA SEMA3B-AS1 (lncRNA SEAS1) in breast cancer progression and the underlying mechanisms. SEAS1 was downregulated in the triple-negative breast cancer (TNBC) tissues compared with the para-carcinoma tissues, which was associated with poor prognosis of TNBC patients. We demonstrated that SEAS1 knockdown significantly increased the proliferation, migration, and invasion of TNBC cell lines, whereas SEAS1 overexpression reversed these effects. Bioinformatics analysis demonstrated that microRNA (miR)-3940-3p was a potential target of SEAS1. Mechanistically, RNA immunoprecipitation (RIP) and luciferase reporter assays confirmed that lncRNA SEMA3B-AS1 acted as sponge for miR-3940-3p, preventing the degradation of its target gene KLLN, which acts as a tumor-inhibiter in TNBC. Moreover, RNA pulldown, mass spectrometry, ChIP, and luciferase reporter assays confirmed that SMAD3 directly interacted with the promoter of SEAS1 and suppressed its transcription, thereby promoting TNBC progression. The clinical samples of TNBC confirmed SEAS1 was correlated inversely with lymphatic and distant metastasis. In conclusion, our findings reveal a novel pathway for TNBC progression via SMAD3/lncRNA SEAS1/miR-3940-3p/KLLN axis, and suggest that SEAS1 may serve as a potential biomarker and therapeutic target for TNBC.
长链非编码 RNA（lncRNA）在各种癌症的进展中发挥着关键的调节作用。然而，lncRNA 在乳腺癌中的功能作用仍不清楚。在这项研究中，我们研究了一种新型长链非编码 RNA SEMA3B-AS1（lncRNA SEAS1）在乳腺癌进展中的功能作用及其潜在机制。与癌旁组织相比，三阴性乳腺癌（TNBC）组织中 SEAS1 的表达下调，与 TNBC 患者的预后不良相关。我们证明，SEAS1 敲低显著增加了 TNBC 细胞系的增殖、迁移和侵袭，而 SEAS1 过表达则逆转了这些效应。生物信息学分析表明，微小 RNA（miR）-3940-3p 是 SEAS1 的一个潜在靶点。机制上，RNA 免疫沉淀（RIP）和荧光素酶报告基因实验证实，lncRNA SEMA3B-AS1 作为 miR-3940-3p 的海绵，阻止了其靶基因 KLLN 的降解，KLLN 在 TNBC 中作为肿瘤抑制因子发挥作用。此外，RNA 下拉、质谱、染色质免疫沉淀和荧光素酶报告基因实验证实，SMAD3 直接与 SEAS1 启动子相互作用，抑制其转录，从而促进 TNBC 的进展。TNBC 的临床样本证实 SEAS1 与淋巴和远处转移呈负相关。总之，我们的研究结果揭示了一个通过 SMAD3/lncRNA SEAS1/miR-3940-3p/KLLN 轴促进 TNBC 进展的新途径，并表明 SEAS1 可能作为 TNBC 的一个潜在的生物标志物和治疗靶点。
