Gene master regulators of papillary and anaplastic thyroid cancers.
Gene master regulators of papillary and anaplastic thyroid cancers.
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乳头状和甲状腺甲状腺癌的基因主调节剂。
DOI：
10.18632/oncotarget.23417
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发表时间：
2018-01-05
期刊：
影响因子：
--
通讯作者：
Tiwari RK
中科院分区：
文献类型：
--
作者：
Iacobas DA;Tuli NY;Iacobas S;Rasamny JK;Moscatello A;Geliebter J;Tiwari RK
我们假设不同的细胞表型是由不同的基因主调节器（GMRs）控制的，这些基因主调节器（GMRs）通过协调来自相应功能途径的众多基因的表达而受到强烈的保护（通过稳态机制）丰度调节大多数细胞过程。引入基因制高点（Gene command Height， GCH）这一基因表达调控与协调的复合测度来建立各表型的基因层次。如果这个假设是正确的，那么人们可以通过改变基因的表达来选择性地破坏来自异质组织的癌结节，这些基因的GCHs在癌症中高，而在正常细胞表型中低。在这里，我们验证了这一假设，并展示了它在甲状腺癌（TC）基因治疗中的实用性。首先，我们证明了手术切除的乳头状TC （PTC）肿瘤的恶性和无癌周围区域由不同的gmr控制。其次，我们表明，在GCH较高的细胞中，基因的稳定转染诱导了更大的转录组改变。为此，我们分析了乳头状BCPAP和间变性8505C TC细胞系稳定转染NEMP1、DDX19B、PANK2或UBALD1前后的转录组。选择转染前在两种细胞系中表达水平相近但GCH评分存在显著差异的4个基因。事实上，这四种基因中的每一种都在细胞中引发了更大的变化，因为它们有更大的GCH。我们的研究结果证明了一种个性化基因治疗方法的可行性，这种方法可以选择性地从组织中靶向癌细胞。
We hypothesize that distinct cell phenotypes are governed by different sets of gene master regulators (GMRs) whose strongly protected (by the homeostatic mechanisms) abundance modulates most cell processes by coordinating the expression of numerous genes from the corresponding functional pathways. Gene Commanding Height (GCH), a composite measure of gene expression control and coordination, is introduced to establish the gene hierarchy in each phenotype. If the hypothesis is true, than one can selectively destroy cancer nodules from a heterogeneous tissue by altering the expression of genes whose GCHs are high in cancer but low in normal cell phenotype. Here, we test the hypothesis and show its utility for the thyroid cancer (TC) gene therapy. First, we prove that malignant and cancer free surrounding areas of a surgically removed papillary TC (PTC) tumor are governed by different GMRs. Second, we show that stable transfection of a gene induces larger transcriptomic alterations in the cells where it has higher GCH than in other cells. For this, we profiled the transcriptomes of the papillary BCPAP and anaplastic 8505C TC cell lines before and after stable transfection with NEMP1, DDX19B, PANK2 or UBALD1. The four genes were selected to have similar expression levels but significantly different GCH scores in the two cell lines before transfection. Indeed, each of the four genes triggered larger alterations in the cells where they had larger GCH. Our results prove the feasibility of a personalized gene therapy approach that selectively targets the cancer cells from a tissue.
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