Comparison of liver oncogenic potential among human RAS isoforms

Comparison of liver oncogenic potential among human RAS isoforms
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DOI：
10.18632/oncotarget.6931
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发表时间：
2016-02-09
期刊：
ONCOTARGET
影响因子：
--
通讯作者：
Ro, Simon Weonsang
Ro, Simon Weonsang
中科院分区：
其他
文献类型：
--
作者：
Chung, Sook In;Moon, Hyuk;Ro, Simon Weonsang

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三个RAS基因(即HRAS、KRAS和NRAS)中的一个突变导致RAS信号通路的结构性激活被认为是人类癌症发生中的一个关键致癌事件。激活的RAS亚型是否具有不同的致癌潜能仍是一个悬而未决的问题。在这里，我们使用小鼠肝脏特异性转基因技术比较了不同RAS亚型的致癌特性。用表达短发夹状RNA的转座子下调P53和激活的RAS亚型，进行流体动力转染，在基因导入后23d取肝脏。表达HRAS(Q61L)、KRAS4B(G12V)和NRAS(Q61K)的小鼠的肝脏大体检查和肝重/体重比(LW/BW)表明，不同RAS亚型的致癌潜能没有差异。然而，不同的KRAS剪接变异体之间的致瘤潜力存在显著差异。KRAS4A(G12V)小鼠的LW/BW比值显著低于KRAS4B(G12V)小鼠(P&lt；0.001)，KRAS4A(G12V)小鼠的寿命显著长于KRRAS4B(G12V)小鼠(P&lt；0.0001)。值得注意的是，与KRAS4B(G12V)肿瘤相比，KRAS4A(G12V)小鼠的肿瘤显示出更高的p16(Ink4A)肿瘤抑制因子的表达。强制过表达p16(Ink4a)显著降低了KRAS4B(G12V)小鼠的肿瘤生长，提示KRAS4A(G12V)上调p16(Ink4a)可能延缓了后者癌基因驱动的肿瘤发展。
Mutation in one of three RAS genes (i.e., HRAS, KRAS, and NRAS) leading to constitutive activation of RAS signaling pathways is considered a key oncogenic event in human carcinogenesis. Whether activated RAS isoforms possess different oncogenic potentials remains an unresolved question. Here, we compared oncogenic properties among RAS isoforms using liver-specific transgenesis in mice. Hydrodynamic transfection was performed using transposons expressing short hairpin RNA downregulating p53 and an activated RAS isoform, and livers were harvested at 23 days after gene delivery. No differences were found in the hepatocarcinogenic potential among RAS isoforms, as determined by both gross examination of livers and liver weight per body weight ratio (LW/BW) of mice expressing HRAS(Q61L), KRAS4B(G12V) and NRAS(Q61K). However, the tumorigenic potential differed significantly between KRAS splicing variants. The LW/BW ratio in KRAS4A(G12V) mice was significantly lower than in KRAS4B(G12V) mice (p < 0.001), and KRAS4A(G12V) mice lived significantly longer than KRRAS4B(G12V) mice (p < 0.0001). Notably, tumors from KRAS4A(G12V) mice displayed higher expression of the p16(INK4A) tumor suppressor when compared with KRAS4B(G12V) tumors. Forced overexpression of p16(INK4A) significantly reduced tumor growth in KRAS4B(G12V) mice, suggesting that upregulation of p16(INK4A) by KRAS4A(G12V) presumably delays tumor development driven by the latter oncogene.