Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India.
J R Soc Interface. 2023 Nov;20(208):20230389. doi: 10.1098/rsif.2023.0389. Epub 2023 Nov 15.
Epithelial-mesenchymal transition (EMT) is an important axis of phenotypic plasticity-a hallmark of cancer metastasis. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their roles in mediating EMT and associated other axes of plasticity remains unclear. Here, analysing transcriptomic data, we reveal their antagonistic trends in a pan-cancer manner in terms of association with EMT, metabolic reprogramming and immune evasion via PD-L1. Next, we developed and simulated a mechanism-based gene regulatory network that captures how RKIP and BACH1 engage in feedback loops with drivers of EMT and stemness. We found that RKIP and BACH1 belong to two antagonistic 'teams' of players-while BACH1 belonged to the one driving pro-EMT, stem-like and therapy-resistant cell states, RKIP belonged to the one enabling pro-epithelial, less stem-like and therapy-sensitive phenotypes. Finally, we observed that low RKIP levels and upregulated BACH1 levels associated with worse clinical outcomes in many cancer types. Together, our systems-level analysis indicates that the emergent dynamics of underlying regulatory network enable the antagonistic patterns of RKIP and BACH1 with various axes of cancer cell plasticity, and with patient survival data.
上皮-间充质转化 (EMT) 是表型可塑性的重要轴——癌症转移的标志。Raf 激酶-B 抑制剂蛋白 (RKIP) 和 BTB 和 CNC 同源 1 (BACH1) 据报道影响 EMT。在乳腺癌中，它们表现出拮抗作用，但它们在介导 EMT 及其相关可塑性轴方面的确切作用仍不清楚。在这里，我们通过分析转录组数据，以泛癌的方式揭示了它们在 EMT、代谢重编程和通过 PD-L1 逃避免疫方面的关联的拮抗趋势。接下来，我们开发并模拟了一个基于机制的基因调控网络，该网络捕捉了 RKIP 和 BACH1 如何与 EMT 和干性的驱动因素进行反馈回路的相互作用。我们发现 RKIP 和 BACH1 属于两个拮抗的“团队”——虽然 BACH1 属于驱动 EMT、类干细胞和抗治疗细胞状态的团队，而 RKIP 属于促进上皮、较少类干细胞和治疗敏感表型的团队。最后，我们观察到在许多癌症类型中，低 RKIP 水平和上调的 BACH1 水平与更差的临床结果相关。总之，我们的系统水平分析表明，基础调控网络的涌现动态使 RKIP 和 BACH1 与癌症细胞可塑性的各种轴以及与患者生存数据呈现出拮抗模式。
