Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, 625021, India.
Funct Integr Genomics. 2022 Dec;22(6):1345-1360. doi: 10.1007/s10142-022-00894-0. Epub 2022 Aug 21.
Deregulated transcription programs and signaling pathways are the critical factors involved in the process of carcinogenesis. Signaling pathway-based classification of tumors is expected to pave the way for the development of targeted therapeutics. We investigated the OCT4-mediated transcription program in the gene expression profiles of 939 gastric tumor samples. A set of 84 genes showing positive correlation with the activation pattern of the available OCT4 gene sets were found to consistently express in diffuse, poorly differentiated, and stage-III gastric tumors with poor prognosis. We also developed stable OCT4-silenced gastric cancer cells and the resultant gene expression changes were investigated by genome-wide mRNA profiling. Functional genomic investigation of the genes downregulated in OCT4-silenced cells and the pathways co-activated with OCT4 gene set across gastric tumors revealed the positive association of dysregulated OCT4 with TGF-β, GLI, PRC2/EzH2, Wnt, KRAS, STK33, and YAP signaling pathways in diffuse subtype gastric tumors. Elevated expression of OCT4 gene set was identified to represent the previously described EMT_UP as well as the GENOMICALLY STABLE subtypes of gastric tumors. Integrative genomic screening of the drug sensitivity of gastric cancer cells in correlation with the expression of OCT4 gene set across drug sensitivity databases revealed the inhibitors of tyrosine kinases, HDAC, and HSP90 to have a negative correlation and needs to be investigated for their potential therapeutic features for the subset of OCT4-activated gastric tumors. Thus, the subset of gastric tumors with OCT4 activation, the associated oncogenic signaling pathways, and potential therapeutic candidates were identified for the development of targeted therapeutic strategies.
失调的转录程序和信号通路是癌症发生过程中涉及的关键因素。基于信号通路的肿瘤分类有望为靶向治疗的发展铺平道路。我们研究了 939 个胃肿瘤样本的基因表达谱中 OCT4 介导的转录程序。一组与现有 OCT4 基因集的激活模式呈正相关的 84 个基因，在弥漫性、低分化和 III 期预后不良的胃肿瘤中持续表达。我们还开发了稳定的 OCT4 沉默胃癌细胞，并通过全基因组 mRNA 谱分析研究了由此产生的基因表达变化。下调 OCT4 沉默细胞中的基因和与 OCT4 基因集在胃肿瘤中共同激活的途径的功能基因组研究表明，失调的 OCT4 与 TGF-β、GLI、PRC2/EzH2、Wnt、KRAS、STK33 和 YAP 信号通路在弥漫性亚型胃肿瘤中呈正相关。OCT4 基因集的高表达被确定为代表先前描述的 EMT_UP 以及胃肿瘤的基因组稳定亚型。通过整合基因组筛选与药物敏感性数据库中 OCT4 基因集表达相关的胃癌细胞对药物的敏感性，发现酪氨酸激酶、HDAC 和 HSP90 的抑制剂呈负相关，需要对其用于 OCT4 激活型胃肿瘤的潜在治疗特征进行研究。因此，确定了具有 OCT4 激活的胃肿瘤亚组、相关致癌信号通路和潜在的治疗候选物，以开发靶向治疗策略。
