PDF(Pubmed)
Abstract：
Patients with non-small cell lung cancer (NSCLC) are often treated with chemotherapy. Poor clinical response and the onset of chemoresistance limit the anti-tumor benefits of drugs such as cisplatin. According to recent research, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA related to cisplatin resistance in NSCLC. Furthermore, MALAT1 targets microRNA-145-5p (miR-145), which activates Krüppel-like factor 4 (KLF4) in associated cell lines. B lymphoma Mo-MLV insertion region 1 homolog (BMI1), on the other hand, inhibits miR-145 expression, which stimulates Specificity protein 1 (Sp1) to trigger the epithelial-mesenchymal transition (EMT) process in pemetrexed-resistant NSCLC cells. The interplay between these molecules in drug resistance is still unclear. Therefore, we propose a dynamic Boolean network that can encapsulate the complexity of these drug-resistant molecules. Using published clinical data for gain or loss-of-function perturbations, our network demonstrates reasonable agreement with experimental observations. We identify four new positive circuits: miR-145/Sp1/MALAT1, BMI1/miR-145/Myc, KLF4/p53/miR-145, and miR-145/Wip1/p38MAPK/p53. Notably, miR-145 emerges as a central player in these regulatory circuits, underscoring its pivotal role in NSCLC drug resistance. Our circuit perturbation analysis further emphasizes the critical involvement of these new circuits in drug resistance for NSCLC. In conclusion, targeting MALAT1 and BMI1 holds promise for overcoming drug resistance, while activating miR-145 represents a potential strategy to significantly reduce drug resistance in NSCLC.
摘要：
非小细胞肺癌（NSCLC）患者通常接受化疗。不良的临床反应和化学抗性的发作限制了药物如顺铂的抗肿瘤益处。根据最近的研究,转移相关肺腺癌转录本1(MALAT1)是一种与NSCLC顺铂耐药相关的长链非编码RNA。此外，MALAT1靶向microRNA-145-5p（miR-145），在相关细胞系中激活Krüppel样因子4（KLF4）。B淋巴瘤Mo-MLV插入区1同源物（BMI1），另一方面,抑制miR-145表达，刺激特异性蛋白1（Sp1）触发培美曲塞耐药NSCLC细胞的上皮-间质转化（EMT）过程。这些分子在耐药性中的相互作用尚不清楚。因此,我们提出了一个动态布尔网络，可以封装这些耐药分子的复杂性。使用已发布的临床数据来获得或失去功能扰动，我们的网络与实验观察结果证明了合理的一致性。我们确定了四个新的阳性回路：miR-145/Sp1/MALAT1，BMI1/miR-145/Myc，KLF4/p53/miR-145和miR-145/Wip1/p38MAPK/p53。值得注意的是,miR-145成为这些调节回路中的核心角色，强调其在NSCLC耐药中的关键作用。我们的电路扰动分析进一步强调了这些新电路在NSCLC耐药性中的关键参与。总之,靶向MALAT1和BMI1有望克服耐药性，而激活miR-145代表了显著降低NSCLC耐药的潜在策略。
