Molecular pathways undergoing dramatic transcriptomic changes during tumor development in the human colon
Molecular pathways undergoing dramatic transcriptomic changes during tumor development in the human colon
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DOI：
10.1186/1471-2407-12-608
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发表时间：
2012-12-19
期刊：
影响因子：
3.8
通讯作者：
Ancona, Nicola
中科院分区：
文献类型：
--
作者：
Maglietta, Rosalia;Liuzzi, Vania Cosma;Ancona, Nicola
背景资料：大肠癌前病变的恶性转化涉及分子和形态学水平的进行性改变，后者包括大小和细胞凋亡程度的增加。因此，分析不同大小的预侵袭性肿瘤可以揭示这些alternation.Methods的序列：我们使用了一种分子通路为基础的方法来分析转录组学的59结直肠肿瘤代表早期和晚期的预侵袭性阶段和肿瘤发生的侵袭性阶段。随机集分析，以确定生物学途径丰富的基因差异调节肿瘤（与59例正常粘膜）。结果：880个典型的途径，我们调查，112个显示显着的肿瘤相关的上调或下调在一个或多个阶段的肿瘤发生。这使我们能够区分在整个肿瘤发生过程中可能需要失调的通路和那些参与特别驱动从一个阶段到下一个阶段进展的通路。我们还能够确定每个基因组中的特定变化，这些变化似乎在每次转变中起着关键作用。早期浸润前阶段的特征是由DNA复制应激触发的细胞周期检查点激活和维持正常粘膜上皮/基质稳态的基本跨膜信号传导过程的显著下调。在晚期浸润前病变中，也有信号转导通路下调（如。例如，在一个实施例中，由G蛋白和核激素受体介导的那些）参与细胞分化和控制核膜动力学和细胞周期中G2> M转换的途径的上调。侵袭阶段的主要特征是细胞周期中G1>S转换的激活，促肿瘤微环境因子的表达上调，以及代谢途径的严重失调（例如，细胞周期中G1> S转换的激活）。例如，在一个实施例中，增加有氧糖酵解，下调代谢药物和外源性物质的途径）。结论：我们的分析揭示了特定的途径，其失调可能在转化过程的每个转变中发挥作用。这是第一个研究中，这种方法已被用来获得进一步了解结直肠肿瘤的发生。因此，这些数据提供了一个发射台进一步探索的分子特征的结直肠肿瘤发生系统生物学方法。
Background: The malignant transformation of precancerous colorectal lesions involves progressive alterations at both the molecular and morphologic levels, the latter consisting of increases in size and in the degree of cellular atypia. Analyzing preinvasive tumors of different sizes can therefore shed light on the sequence of these alterations.Methods: We used a molecular pathway-based approach to analyze transcriptomic profiles of 59 colorectal tumors representing early and late preinvasive stages and the invasive stage of tumorigenesis. Random set analysis was used to identify biological pathways enriched for genes differentially regulated in tumors (compared with 59 samples of normal mucosa).Results: Of the 880 canonical pathways we investigated, 112 displayed significant tumor-related upregulation or downregulation at one or more stages of tumorigenesis. This allowed us to distinguish between pathways whose dysregulation is probably necessary throughout tumorigenesis and those whose involvement specifically drives progression from one stage to the next. We were also able to pinpoint specific changes within each gene set that seem to play key roles at each transition. The early preinvasive stage was characterized by cell-cycle checkpoint activation triggered by DNA replication stress and dramatic downregulation of basic transmembrane signaling processes that maintain epithelial/stromal homeostasis in the normal mucosa. In late preinvasive lesions, there was also downregulation of signal transduction pathways (e. g., those mediated by G proteins and nuclear hormone receptors) involved in cell differentiation and upregulation of pathways governing nuclear envelope dynamics and the G2> M transition in the cell cycle. The main features of the invasive stage were activation of the G1>S transition in the cell cycle, upregulated expression of tumor-promoting microenvironmental factors, and profound dysregulation of metabolic pathways (e. g., increased aerobic glycolysis, downregulation of pathways that metabolize drugs and xenobiotics).Conclusions: Our analysis revealed specific pathways whose dysregulation might play a role in each transition of the transformation process. This is the first study in which such an approach has been used to gain further insights into colorectal tumorigenesis. Therefore, these data provide a launchpad for further exploration of the molecular characterization of colorectal tumorigenesis using systems biology approaches.