Genomic imprinting and Igf2 influence liver tumorigenesis and loss of heterozygosity in SV40 T antigen transgenic mice.
Genomic imprinting and Igf2 influence liver tumorigenesis and loss of heterozygosity in SV40 T antigen transgenic mice.
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发表时间：
1997-10
期刊：
影响因子：
11.2
通讯作者：
R. Haddad;W. Held
中科院分区：
文献类型：
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作者：
R. Haddad;W. Held
在SV40 T/ T抗原诱导的肝脏肿瘤中观察到母体特异性杂合性缺失（LOH）和等位基因不平衡[即部分LOH (pLOH)]，这表明7号染色体上的一个印迹基因参与了肝脏肿瘤的发生。母亲特异性LOH/pLOH可能反映了母亲表达的肿瘤抑制基因的缺失或父亲的生长促进子活性等位基因的获得。此外，在SV40 T/ T抗原转基因系（M11T-G）中，7号染色体远端Igf2和H19两个相反的印迹基因在大多数肝脏肿瘤中重新表达。Igf2是父亲表达的生长促进因子，而H19是母亲表达的基因，可以抑制某些肿瘤细胞系的生长。我们通过构建Igf2 (+/-) M11T-G小鼠来研究Igf2在肝脏肿瘤发生中的作用。这些小鼠基本上没有Igf2的表达，因为印迹通常会阻止母体Igf2的表达。M11T-G, Igf2（+/-）男性出现大肿瘤的频率降低了15倍。Igf2（+/-）肿瘤不表达母体Igf2，表明在肝脏中有严格的印迹控制。对肿瘤进行LOH/pLOH分析，表明获得父系活性Igf2等位基因是M11T-G肝肿瘤发生的主要选择性事件。这也意味着在7号染色体上存在一个印迹的、母系表达的肿瘤抑制基因，不太可能是H19。
Maternal-specific loss of heterozygosity (LOH) and allelic imbalances [i.e., partial LOH (pLOH)] observed in SV40 T/t antigen-induced liver tumors suggests that an imprinted gene on chromosome 7 is involved in liver tumorigenesis. Maternal-specific LOH/pLOH may reflect the loss of a maternally expressed tumor suppressor gene or the acquisition of paternally active alleles of a growth promoter. In addition, two oppositely imprinted genes on distal chromosome 7, Igf2 and H19, are re-expressed in most liver tumors from an SV40 T/t antigen transgenic line (M11T-G). Igf2 is a paternally expressed growth promoter, and H19 is a maternally expressed gene that can suppress growth in some tumor cell lines. We studied the role of Igf2 during liver tumorigenesis by creating Igf2 (+/-) M11T-G mice. These mice are essentially null for Igf2 expression because imprinting normally precludes maternal Igf2 expression. M11T-G, Igf2 (+/-) males exhibit a 15-fold reduction in the frequency of large tumors. Igf2 (+/-) tumors do not express maternal Igf2, indicating rigid imprinting control in the liver. LOH/pLOH analysis was performed on the tumors and indicates that acquisition of paternally active Igf2 alleles is a major selective event for M11T-G liver tumorigenesis. This also implies the existence of an imprinted, maternally expressed tumor suppressor gene on chromosome 7 that is unlikely to be H19.