Specific genomic and transcriptomic aberrations in tumors induced by partial hepatectomy of a chronically inflamed murine liver
Specific genomic and transcriptomic aberrations in tumors induced by partial hepatectomy of a chronically inflamed murine liver
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DOI：
10.18632/oncotarget.2515
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发表时间：
2014-11-15
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影响因子：
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通讯作者：
Goldenberg, Daniel
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作者：
Ella, Ezra;Heim, Denise;Goldenberg, Daniel
肝部分切除术(PHX)切除肝细胞癌(HCC)与促进肝癌的发生有关。我们之前已经报道过PHX促进mdr2基因敲除(mdr2-KO)小鼠的肝癌发生，mdr2-KO是一种炎症介导的肝癌模型。现在，为了探索PHX促进肿瘤作用的分子机制，我们比较了在mdr2-KO小鼠中自发和跟随PHX发展的肝癌肿瘤的基因组和转录图谱。PHX使这些小鼠的肝癌发展速度加快了四个月。PHX诱导的肿瘤有主要的染色体异常：都是影响多条染色体的扩增。这些扩增大多位于小鼠染色体的着丝粒附近。四个不同的染色体区域分别在至少三个肿瘤中被扩增。这些常见扩增区域的人类同源基因已知在肝细胞癌中扩增。未经治疗的小鼠的所有肿瘤都有染色体异常，包括缺失和扩增。自发性肿瘤中的扩增影响较少的染色体，并且不优先位于染色体边缘。基因表达谱的比较显示，与自发肿瘤相比，PHX术后的癌基因、染色体不稳定标记和E2F1靶基因的表达显著丰富。这两组肿瘤在18号染色体上都有相同的频繁扩增。在这里，我们揭示了由该扩增区域编码的调节基因之一CREM在体内的小鼠和人肝癌细胞的细胞核中过表达，并在体外刺激了人肝癌细胞的增殖。我们的结果表明，慢性炎症肝脏的PHX将肿瘤的发展引导到一个离散的途径，其特征是特定染色体区域的放大和特定肿瘤促进基因的表达。CREM是一种新的候选癌基因，在该模型中经常被扩增，在人肝细胞癌中也经常过表达。
Resection of hepatocellular carcinoma (HCC) tumors by partial hepatectomy (PHx) is associated with promoting hepatocarcinogenesis. We have previously reported that PHx promotes hepatocarcinogenesis in the Mdr2-knockout (Mdr2-KO) mouse, a model for inflammation-mediated HCC. Now, to explore the molecular mechanisms underlying the tumor-promoting effect of PHx, we compared genomic and transcriptomic profiles of HCC tumors developing in the Mdr2-KO mice either spontaneously or following PHx. PHx accelerated HCC development in these mice by four months. PHx-induced tumors had major chromosomal aberrations: all were amplifications affecting multiple chromosomes. Most of these amplifications were located near the acrocentric centromeres of murine chromosomes. Four different chromosomal regions were amplified each in at least three tumors. The human orthologs of these common amplified regions are known to be amplified in HCC. All tumors of untreated mice had chromosomal aberrations, including both deletions and amplifications. Amplifications in spontaneous tumors affected fewer chromosomes and were not located preferentially at the chromosomal edges. Comparison of gene expression profiles revealed a significantly enriched expression of oncogenes, chromosomal instability markers and E2F1 targets in the post-PHx compared to spontaneous tumors. Both tumor groups shared the same frequent amplification at chromosome 18. Here, we revealed that one of the regulatory genes encoded by this amplified region, Crem, was over-expressed in the nuclei of murine and human HCC cells in vivo, and that it stimulated proliferation of human HCC cells in vitro. Our results demonstrate that PHx of a chronically inflamed liver directed tumor development to a discrete pathway characterized by amplification of specific chromosomal regions and expression of specific tumor-promoting genes. Crem is a new candidate HCC oncogene frequently amplified in this model and frequently over-expressed in human HCC.