Department of General Surgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215000, China.
Insitute of Blood Transfusion, Suzhou Blood Center, Suzhou, 215000, China.
Mol Cancer. 2021 Mar 1;20(1):43. doi: 10.1186/s12943-021-01332-8.
Chemotherapeutic resistance is the main cause of clinical treatment failure and poor prognosis in triple-negative breast cancer (TNBC). There is no research on chemotherapeutic resistance in TNBC from the perspective of circular RNAs (circRNAs).
TNBC-related circRNAs were identified based on the GSE101124 dataset. Quantitative reverse transcription PCR was used to detect the expression level of circWAC in TNBC cells and tissues. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circWAC in TNBC.
CircWAC was highly expressed in TNBC and was associated with worse TNBC patient prognosis. Subsequently, it was verified that downregulation of circWAC can increase the sensitivity of TNBC cells to paclitaxel (PTX) in vitro and in vivo. The expression of miR-142 was negatively correlated with circWAC in TNBC. The interaction between circWAC and miR-142 in TNBC cells was confirmed by RNA immunoprecipitation assays, luciferase reporter assays, pulldown assays, and fluorescence in situ hybridization. Mechanistically, circWAC acted as a miR-142 sponge to relieve the repressive effect of miR-142 on its target WWP1. In addition, the overall survival of TNBC patients with high expression of miR-142 was significantly better than that of patients with low expression of miR-142, and these results were verified in public databases. MiR-142 regulated the expression of WWP1 and the activity of the PI3K/AKT pathway. It was confirmed that WWP1 is highly expressed in TNBC and that the prognosis of patients with high WWP1 expression is poor.
CircWAC/miR-142/WWP1 form a competing endogenous RNA (ceRNA) network to regulate PI3K/AKT signaling activity in TNBC cells and affect the chemosensitivity of cells.
化疗耐药是三阴性乳腺癌（TNBC）临床治疗失败和预后不良的主要原因。目前尚无从环状 RNA（circRNA）角度研究 TNBC 化疗耐药的相关研究。
基于 GSE101124 数据集鉴定与 TNBC 相关的 circRNA。采用实时定量逆转录 PCR 检测 circWAC 在 TNBC 细胞和组织中的表达水平。然后，通过体外和体内功能实验评估 circWAC 在 TNBC 中的作用。
circWAC 在 TNBC 中高表达，与 TNBC 患者预后不良相关。随后，验证下调 circWAC 可增加 TNBC 细胞对紫杉醇（PTX）的体外和体内敏感性。在 TNBC 中，circWAC 的表达与 miR-142 呈负相关。通过 RNA 免疫沉淀实验、荧光素酶报告基因实验、下拉实验和荧光原位杂交实验证实了 circWAC 在 TNBC 细胞中的相互作用。机制上，circWAC 作为 miR-142 的海绵体，减轻了 miR-142 对其靶基因 WWPI 的抑制作用。此外，miR-142 高表达的 TNBC 患者的总生存率明显优于 miR-142 低表达的患者，这一结果在公共数据库中得到了验证。miR-142 调节 WWPI 的表达和 PI3K/AKT 通路的活性。证实 WWPI 在 TNBC 中高表达，且 WWPI 高表达的患者预后不良。
circWAC/miR-142/WWP1 形成竞争性内源 RNA（ceRNA）网络，调节 TNBC 细胞中 PI3K/AKT 信号活性，影响细胞的化疗敏感性。
