Cancer Institute, Fudan University Shanghai Cancer Center and Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cancer Institute, Fudan University Shanghai Cancer Center and Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Cancer Lett. 2023 Jul 1;565:216241. doi: 10.1016/j.canlet.2023.216241. Epub 2023 May 20.
Platinum-taxane chemotherapy is the first-line standard-of-care treatment administered to patients with epithelial ovarian cancer (EOC), and faces the major challenge of cisplatin resistance. Aurora Kinase A (AURKA) is a serine/threonine kinase, acting as an oncogene by participating in microtubule formation and stabilization. In this study, we demonstrate that AURKA binds with DDX5 directly to form a transcriptional coactivator complex to induce the transcription and upregulation of an oncogenic long non-coding RNA, TMEM147-AS1, which sponges hsa-let-7b/7c-5p leading to the increasing expression of AURKA as a feedback loop. The feedback loop maintains EOC cisplatin resistance via activation of lipophagy. These findings underscore the feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 provides mechanistic insights into the combined use of TMEM147-AS1 siRNA and VX-680, which can help improve EOC cisplatin treatment. Our mathematical model shows that the feedback loop has the potential to act as a biological switch to maintain on- (activated) or off- (deactivated) status, implying the possible resistance of single use of VX-680 or TMEM147-AS1 siRNA. The combined use reduces both the protein level of AURKA using TMEM147-AS1 siRNA and its kinase activity using VX-680, showing more significant effect than the use of TMEM147-AS1 siRNA or VX-680 alone, which provides a potential strategy for EOC treatment.
铂类紫杉烷化疗是上皮性卵巢癌 (EOC) 患者的一线标准治疗方法，但面临顺铂耐药的主要挑战。极光激酶 A (AURKA) 是一种丝氨酸/苏氨酸激酶，通过参与微管形成和稳定，作为癌基因发挥作用。在这项研究中，我们证明 AURKA 与 DDX5 直接结合形成转录共激活复合物，诱导致癌长非编码 RNA TMEM147-AS1 的转录和上调，该 RNA 作为海绵吸附 hsa-let-7b/7c-5p，导致 AURKA 的表达增加作为反馈环。该反馈环通过激活脂噬作用维持 EOC 顺铂耐药性。这些发现强调了 AURKA/DDX5/TMEM147-AS1/let-7 的反馈环为联合使用 TMEM147-AS1 siRNA 和 VX-680 提供了机制见解，这有助于改善 EOC 顺铂治疗。我们的数学模型表明，该反馈环具有作为生物开关的潜力，以维持开（激活）或关（失活）状态，这意味着单独使用 VX-680 或 TMEM147-AS1 siRNA 可能存在耐药性。联合使用 TMEM147-AS1 siRNA 降低 AURKA 的蛋白水平，使用 VX-680 降低其激酶活性，比单独使用 TMEM147-AS1 siRNA 或 VX-680 更有效，为 EOC 治疗提供了一种潜在策略。
