Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, Ontario, Canada.
Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.
J Cell Mol Med. 2022 Apr;26(7):2049-2062. doi: 10.1111/jcmm.17228. Epub 2022 Mar 1.
Through a comprehensive review and in silico analysis of reported data on STAT-linked diseases, we analysed the communication pathways and interactome of the seven STATs in major cancer categories and proposed rational targeting approaches for therapeutic intervention to disrupt critical pathways and addictions to hyperactive JAK/STAT in neoplastic states. Although all STATs follow a similar molecular activation pathway, STAT1, STAT2, STAT4 and STAT6 exert specific biological profiles associated with a more restricted pattern of activation by cytokines. STAT3 and STAT5A as well as STAT5B have pleiotropic roles in the body and can act as critical oncogenes that promote many processes involved in cancer development. STAT1, STAT3 and STAT5 also possess tumour suppressive action in certain mutational and cancer type context. Here, we demonstrated member-specific STAT activity in major cancer types. Through systems biology approaches, we found surprising roles for EGFR family members, sex steroid hormone receptor ESR1 interplay with oncogenic STAT function and proposed new drug targeting approaches of oncogenic STAT pathway addiction.
通过对已报道的 STAT 相关疾病数据进行全面回顾和计算机分析，我们分析了七种 STAT 在主要癌症类别中的信号通路和相互作用组，并提出了合理的靶向治疗方法，以阻断致癌状态下 JAK/STAT 的异常激活和关键通路。虽然所有 STAT 都遵循相似的分子激活途径，但 STAT1、STAT2、STAT4 和 STAT6 具有特定的生物学特征，与细胞因子的激活模式更为受限有关。STAT3 和 STAT5A 以及 STAT5B 在体内具有多效性作用，可作为促进癌症发展过程中许多涉及的关键癌基因。STAT1、STAT3 和 STAT5 在某些突变和癌症类型的背景下也具有肿瘤抑制作用。在这里，我们展示了主要癌症类型中特定 STAT 的活性。通过系统生物学方法，我们发现了 EGFR 家族成员、性激素激素受体 ESR1 与致癌 STAT 功能相互作用的惊人作用，并提出了针对致癌 STAT 通路成瘾的新药物靶向治疗方法。
