转录共表达网络揭示了不同胃癌亚型中不同的失调与不同干细胞特征的关联。
Transcriptional coexpression network reveals the involvement of varying stem cell features with different dysregulations in different gastric cancer subtypes.
作者信息
Kalamohan Kalaivani, Periasamy Jayaprakash, Bhaskar Rao Divya, Barnabas Georgina D, Ponnaiyan Srigayatri, Ganesan Kumaresan
机构信息
Cancer Genetics Laboratory, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai 625021, India.
Cancer Genetics Laboratory, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai 625021, India.
出版信息
Mol Oncol. 2014 Oct;8(7):1306-25. doi: 10.1016/j.molonc.2014.04.005. Epub 2014 May 9.
Despite the advancements in the cancer therapeutics, gastric cancer ranks as the second most common cancers with high global mortality rate. Integrative functional genomic investigation is a powerful approach to understand the major dysregulations and to identify the potential targets toward the development of targeted therapeutics for various cancers. Intestinal and diffuse type gastric tumors remain the major subtypes and the molecular determinants and drivers of these distinct subtypes remain unidentified. In this investigation, by exploring the network of gene coexpression association in gastric tumors, mRNA expressions of 20,318 genes across 200 gastric tumors were categorized into 21 modules. The genes and the hub genes of the modules show gastric cancer subtype specific expression. The expression patterns of the modules were correlated with intestinal and diffuse subtypes as well as with the differentiation status of gastric tumors. Among these, G1 module has been identified as a major driving force of diffuse type gastric tumors with the features of (i) enriched mesenchymal, mesenchymal stem cell like, and mesenchymal derived multiple lineages, (ii) elevated OCT1 mediated transcription, (iii) involvement of Notch activation, and (iv) reduced polycomb mediated epigenetic repression. G13 module has been identified as key factor in intestinal type gastric tumors and found to have the characteristic features of (i) involvement of embryonic stem cell like properties, (ii) Wnt, MYC and E2F mediated transcription programs, and (iii) involvement of polycomb mediated repression. Thus the differential transcription programs, differential epigenetic regulation and varying stem cell features involved in two major subtypes of gastric cancer were delineated by exploring the gene coexpression network. The identified subtype specific dysregulations could be optimally employed in developing subtype specific therapeutic targeting strategies for gastric cancer.
尽管癌症治疗取得了进展，但胃癌仍是全球死亡率很高的第二大常见癌症。综合功能基因组研究是一种强大的方法，可用于了解主要的失调情况，并确定针对各种癌症开发靶向治疗的潜在靶点。肠型和弥漫型胃肿瘤仍然是主要亚型，而这些不同亚型的分子决定因素和驱动因素仍未明确。在这项研究中，通过探索胃肿瘤中的基因共表达关联网络，将200个胃肿瘤中20318个基因的mRNA表达分为21个模块。这些模块的基因和枢纽基因显示出胃癌亚型特异性表达。这些模块的表达模式与肠型和弥漫型亚型以及胃肿瘤的分化状态相关。其中，G1模块已被确定为弥漫型胃肿瘤的主要驱动力，其特征为：（i）富含间充质、间充质干细胞样和间充质衍生的多个谱系；（ii）OCT1介导的转录升高；（iii）Notch激活的参与；（iv）多梳介导的表观遗传抑制降低。G13模块已被确定为肠型胃肿瘤的关键因素，并发现具有以下特征：（i）涉及胚胎干细胞样特性；（ii）Wnt、MYC和E2F介导的转录程序；（iii）多梳介导的抑制的参与。因此，通过探索基因共表达网络，描绘了胃癌两种主要亚型中涉及的差异转录程序、差异表观遗传调控和不同的干细胞特征。所确定的亚型特异性失调可最佳地用于开发针对胃癌的亚型特异性治疗靶向策略。
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