Department of Breast Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Breast, Fujian Provincial Maternity and Children's Hospital of Fujian Medical University, Fuzhou 350000, China.
Department of Physiology, Zhongshan Medical School, Sun Yat-sen University, Guangzhou 510060, China.
Mol Ther. 2021 Jan 6;29(1):244-262. doi: 10.1016/j.ymthe.2020.09.005. Epub 2020 Sep 5.
Metastatic tumor is a major contributor to death caused by breast cancer. However, effective and targeted therapy for metastatic breast cancer remains to be developed. Initially, we exploited a feasible biological rationale of the association between metastatic status and tumor-initiating properties in metastatic breast cancer stem cells (BCSCs). Further, we explored that circular RNA RANBP2-like and GRIP domain-containing protein 6 (circRGPD6) regulates the maintenance of stem cell-like characteristics of BCSCs. Targeted expression of circRGPD6 via human telomerase reverse transcriptase (hTERT) promoter-driven VP16-GAL4-woodchuck hepatitis virus post-transcriptional regulatory element (WPRE)-integrated systemic amplifier delivery composite vector (TV-circRGPD6) significantly inhibited expression of stem-cell marker CD44 and increased expression of the DNA damage marker p-H2AX. Furthermore, we determined TV-circRGPD6, alone or synergized with docetaxel, displays significant therapeutic responses on metastatic BCSCs. Mechanistic analyses exploited that TV-circRGPD6 suppresses BCSC-mediated metastasis via the microRNA (miR)-26b/YAF2 axis. Clinically, for the first time, we observed that expressions of circRGPD6 and YAF2 predict a favorable prognosis in patients with breast cancer, whereas expression of miR-26b is an unfavorable prognostic factor. Overall, we have developed a TV-circRGPD6 nanoparticle that selectively expresses circRGPD6 in metastatic BCSCs to eradicate breast cancer metastasis, therefore providing a novel avenue to treat breast cancers.
转移性肿瘤是导致乳腺癌死亡的主要原因。然而，转移性乳腺癌的有效和靶向治疗仍有待开发。最初，我们利用转移性和肿瘤起始特性之间的关联的可行生物学原理，研究转移性乳腺癌干细胞（BCSCs）中的转移性肿瘤。此外，我们发现环状 RNA RANBP2 样和 GRIP 结构域蛋白 6（circRGPD6）调节 BCSC 干细胞样特征的维持。通过人端粒酶逆转录酶（hTERT）启动子驱动的 VP16-GAL4-woodchuck hepatitis virus 转录后调节元件（WPRE）-整合的系统放大器递送复合载体（TV-circRGPD6）靶向表达 circRGPD6，显著抑制了干细胞标记物 CD44 的表达，并增加了 DNA 损伤标记物 p-H2AX 的表达。此外，我们确定 TV-circRGPD6 单独或与多西紫杉醇协同作用，对转移性 BCSC 显示出显著的治疗反应。机制分析利用 TV-circRGPD6 通过 microRNA（miR）-26b/YAF2 轴抑制 BCSC 介导的转移。临床上，我们首次观察到 circRGPD6 和 YAF2 的表达可预测乳腺癌患者的预后良好，而 miR-26b 的表达是预后不良的因素。总之，我们开发了一种 TV-circRGPD6 纳米颗粒，可在转移性 BCSC 中选择性表达 circRGPD6，以根除乳腺癌转移，从而为治疗乳腺癌提供了新途径。
