Haier Jörg, Ströse Anda, Matuszcak Christiane, Hummel Richard
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Martinistr. 52, Building O24, 20246, Hamburg, Germany.
Comprehensive Cancer Center Münster (CCCM), University Hospital Münster, Münster, Germany.
Cancer Metastasis Rev. 2016 Jun;35(2):289-322. doi: 10.1007/s10555-016-9617-1.
Using the two paralog miR-23∼27∼24 clusters as an example and combining experimental and clinical data in a systematical approach to microRNA (miR) function and dysregulation, a complex picture of their roles in cancer is drawn. Various findings appear to be contradictory to a larger extent and cannot be fully explained by the classical regulatory network models and feedback loops that are mainly considered by one-to-one regulatory interactions of the involved molecules. Here, we propose an extended model of the regulatory role of miRs that, at least, supplements the usually considered single/oligo-target regulation of certain miRs. The cellular availability of the participating miR members in this model reflects an upper hierarchy level of intracellular and extracellular environmental influences, such as neighboring cells, soluble factors, hypoxia, chemotherapeutic drugs, and irradiation, among others. The novel model is based on the understanding of cellular functional complexes, such as for apoptosis, migration, and proliferation. These complexes consist of many regulatory components that can be targeted by miR cluster members to a different extent but may affect the functional complex in different ways. We propose that the final miR-related effect is a result of the possible degree of regulatory freedom provided by the miR effects on the whole functional complex structure. This degree of regulatory freedom defines to which extent the cellular functional complex can react in response to regulatory triggers, also understood as sensitization (more regulatory response options) or de-sensitization (less regulatory response options) of the system rather than single molecules.
以两个旁系同源物miR - 23∼27∼24簇为例，并以系统的方法结合实验和临床数据来研究微小RNA（miR）的功能和失调，描绘出了它们在癌症中作用的复杂图景。各种研究结果在很大程度上似乎相互矛盾，并且不能用经典的调控网络模型和反馈回路来完全解释，这些模型和回路主要考虑的是相关分子的一对一调控相互作用。在这里，我们提出了一个miR调控作用的扩展模型，该模型至少补充了通常所考虑的某些miR的单/寡靶点调控。此模型中参与的miR成员的细胞可用性反映了细胞内和细胞外环境影响的更高层次，如邻近细胞、可溶性因子、缺氧、化疗药物和辐射等。这个新模型基于对细胞功能复合物的理解，如凋亡、迁移和增殖相关的复合物。这些复合物由许多调控成分组成，miR簇成员可以不同程度地靶向这些成分，但可能以不同方式影响功能复合物。我们提出，最终的miR相关效应是miR对整个功能复合物结构的作用所提供的可能调控自由度的结果。这种调控自由度定义了细胞功能复合物在响应调控触发因素时能够做出反应的程度，这也被理解为系统的敏化（更多调控反应选项）或脱敏（更少调控反应选项），而不是单个分子的情况。
