化学肝癌发生的基因组和转录组分析因癌蛋白损失而加剧
Genomic and transcriptomic analyses of chemical hepatocarcinogenesis aggravated by oncoprotein loss
影响因子:15.80000
分区:医学1区 Top / 胃肠肝病学1区
发表日期:2025 Apr 01
作者:
Xinyi Wang, Yingluo Liu, Shuo Zhang, Jiemeng Zhang, Xiaoxue Lin, Yan Liang, Min Zong, Kaisa L Hanley, Jin Lee, Michael Karin, Gen-Sheng Feng
摘要
化学致癌二乙基硝基胺（DEN）通常用于诱导小鼠中的HCC。奇怪的是，一些实验室报告说，从肝细胞中去除癌蛋白加剧了DEN诱导的HCC，机制未知。 This study aimed at deciphering molecular mechanisms underlying the tumor suppressive effect of oncoproteins.We generated mutant mouse lines with hepatocyte-specific deletions of Met , Ptpn11 / Shp2 , Ikkβ , or Ctnnb1/β-catenin and assessed DEN-induced tumorigenesis in the wild-type and mutant mice.为了系统地检查遗传和分子信号传导的改变，我们对在癌症和建立的癌症阶段收集的肝样品进行了整个外显子组和RNA顺序。尽管在野生型和突变小鼠中，DEN诱导的肿瘤的突变谱几乎没有不同，但肿瘤蛋白消融增加了DEN诱导的突变负担，尤其是在SHP2缺陷型肿瘤中。 RNA测序显示信号通路的多次变化，特别是上调上调的上层间质转变，细胞迁移和肿瘤转移，以及下调受癌蛋白消融影响的小分子代谢。我们确定了与肝固有免疫相关并与肝肿瘤发生有关的关键分子和途径。此外，我们在人类HCC数据库中明显改变了一些miRNA的表达。在肿瘤蛋白消融上看到的DEN诱导的HCC进展的加剧可能是由常见和独特的基因组和信号变化引起的。这项研究揭示了肝癌发生的新复杂程度，并阐明了肿瘤进化和复发的分子机制。
Abstract
The chemical carcinogen diethylnitrosamine (DEN) is often used to induce HCC in mice. Curiously, several labs have reported that the removal of oncoproteins from hepatocytes exacerbated DEN-induced HCC, with mechanisms unknown. This study aimed at deciphering molecular mechanisms underlying the tumor suppressive effect of oncoproteins.We generated mutant mouse lines with hepatocyte-specific deletions of Met , Ptpn11 / Shp2 , Ikkβ , or Ctnnb1/β-catenin and assessed DEN-induced tumorigenesis in the wild-type and mutant mice. To systematically examine genetic and molecular signaling alterations, we performed whole exome and RNA-sequencing on liver samples collected at the pre-cancer and established cancer stages. Although the mutational profiles of DEN-induced tumors were barely different in wild-type and mutant mice, oncoprotein ablation increased DEN-induced mutational burdens, especially in Shp2-deficient tumors. RNA-sequencing revealed multiple changes in signaling pathways, in particular, upregulated epithelial-mesenchymal transition, cell migration, and tumor metastasis, as well as downregulated small molecule metabolism that was affected by oncoprotein ablation. We identified key molecules and pathways that are associated with hepatic innate immunity and implicated in liver tumorigenesis. In addition, we unveiled markedly changed expression of a few miRNAs in the human HCC database.The aggravation of DEN-induced HCC progression seen on oncoprotein ablation could be caused by common and distinct genomic and signaling alterations. This study reveals a new level of complexity in hepatocarcinogenesis and elucidates molecular mechanisms underlying tumor evolution and recurrence.