Micrbial Biotechnology Department, National Research Center, Dokki, Cairo, 12622, Egypt.
Micrbial Biotechnology Department, National Research Center, Dokki, Cairo, 12622, Egypt.
Gene. 2018 Jul 20;664:58-69. doi: 10.1016/j.gene.2018.04.032. Epub 2018 Apr 21.
Liver fibrosis results from a wound healing response to chronic injury, which leads to excessive matrix deposition. Genome wide association studies have showen transcriptional dysregulation in mild and severe liver fibrosis. Recent studies suggested that genetic markers may be able to define the exact stage of liver fibrosis.
To define genes or genetic pathways that could serve as markers for staging or as therapeutic targets to halt progression of liver fibrosis.
The study was performed on 105 treatment naïve HCV genotype 4 infected patients [F0-F2, n = 56; F3-F4, n = 49] and 16 healthy subjects. The study included PCR array on 84 fibrosis related genes followed by customization of a smaller array consisting of 11 genes that were designed on the bases of results obtained from the larger array. Genes that displayed significant dysregulation at mRNA levels were validated at protein levels.
Two major pathways exhibited high dysregulation in early fibrosis as compared with controls or when compared with late fibrosis, these were the TGFβ - related pathway genes and Matrix - deposition associated genes. Hepatic stellate cell (HSC) activators i.e. TGFβ pathway genes [TGFβ1, 2 and 3, their receptors TGFβR1 and 2, signaling molecules SMAD genes and PDGF growth factors] were considerably over-expressed at transcriptional levels as early as F0, whereas expression of their inhibitor TGIF1 was simultaneously down regulated. Matrix proteins including collagen and MMPs were upregulated in early fibrosis whereas tissue inhibitors TIMPs 1 and 2 began over expression in late fibrosis. Expression at protein levels was concordant with RNA data excluding dysregulation at post transcriptional levels.
Since these 2 gene sets are closely interrelated regarding HSC activation and proliferation, we assume that the current findings suggest that they are favorable targets to further search for stage specific markers.
肝纤维化是由慢性损伤引起的创伤愈合反应导致基质过度沉积所致。全基因组关联研究显示，轻度和重度肝纤维化存在转录失调。最近的研究表明，遗传标志物可能能够确定肝纤维化的确切阶段。
确定可作为分期标志物或作为阻止肝纤维化进展的治疗靶点的基因或遗传途径。
该研究纳入了 105 例未经治疗的 HCV 基因型 4 感染患者[F0-F2，n=56；F3-F4，n=49]和 16 例健康对照者。研究包括 84 个纤维化相关基因的 PCR 阵列，然后定制一个包含 11 个基因的较小阵列，这些基因是基于较大阵列的结果设计的。在蛋白质水平上验证了显示 mRNA 水平显著失调的基因。
与对照组或晚期纤维化相比，早期纤维化中两个主要途径表现出高度失调，这两个途径是 TGFβ 相关途径基因和基质沉积相关基因。肝星状细胞（HSC）激活剂，即 TGFβ 途径基因[TGFβ1、2 和 3、其受体 TGFβR1 和 2、信号分子 SMAD 基因和 PDGF 生长因子]在 F0 时转录水平就明显过表达，而其抑制剂 TGIF1 的表达同时被下调。早期纤维化中基质蛋白包括胶原和 MMPs 上调，而组织抑制剂 TIMPs 1 和 2 开始在晚期纤维化中过表达。蛋白质水平的表达与 RNA 数据一致，排除了转录后水平的失调。
由于这两个基因集在 HSC 激活和增殖方面密切相关，我们假设目前的发现表明它们是进一步寻找分期特异性标志物的有利靶点。
