A bicistronic CYCLIN D1-TROP2 mRNA chimera demonstrates a novel oncogenic mechanism in human cancer
A bicistronic CYCLIN D1-TROP2 mRNA chimera demonstrates a novel oncogenic mechanism in human cancer
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DOI：
10.1158/0008-5472.can-07-6135
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Alberti, Saverio
中科院分区：
文献类型：
--
作者：
Guerra, Emanuela;Trerotola, Marco;Alberti, Saverio
从人卵巢癌和乳腺癌细胞中分离嵌合细胞周期蛋白D1-TROP 2 mRNA。细胞周期蛋白D1-TROP 2 mRNA被证明是一种有效的致癌基因，因为它在体外转化幼稚的原代细胞，并在体内与活化的RAS协同诱导侵袭性肿瘤生长。嵌合mRNA的沉默抑制乳腺癌细胞的生长。所分析的大部分人胃肠道、卵巢和子宫内膜肿瘤表达细胞周期蛋白D1-TROP 2 mRNA。它最常在肠细胞非整倍体癌症中检测到，并且与激活的RAS癌基因共表达，与人类癌症中的协同转化活性一致。嵌合mRNA是转录后来源的双顺反子转录物，其独立地翻译细胞周期蛋白D1和Trop-2蛋白。这是一种新的细胞周期蛋白D1激活机制，在不存在染色体重排的情况下实现细胞周期蛋白D1 mRNA的截短。这导致更高的细胞周期蛋白D1 mRNA稳定性，在细胞周期中不适当的表达。稳定的细胞周期蛋白D1 mRNA与TROP 2协同刺激表达细胞的生长。这些发现显示了一种新的表观遗传致癌机制，似乎在人类癌症中广泛存在。
A chimeric CYCLIN D1-TROP2 mRNA was isolated from human ovarian and mammary cancer cells. The CYCLIN D1-TROP2 mRNA was shown to be a potent oncogene as it transforms naive, primary cells in vitro and induces aggressive tumor growth in vivo in cooperation with activated RAS. Silencing of the chimeric mRNA inhibits the growth of breast cancer cells. The CYCLIN D1-TROP2 mRNA was expressed by a large fraction of the human gastrointestinal, ovarian, and endometrial tumors analyzed. It is most frequently detected in intestinal cell aneuploid cancers and it is coexpressed with activated RAS oncogenes, consistent with a cooperative transforming activity in human cancers. The chimeric mRNA is a bicistronic transcript of posttranscriptional origin that independently translates the Cyclin D1 and Trop-2 proteins. This is a novel mechanism of CYCLIN D1 activation that achieves the truncation of the CYCLIN D1 mRNA in the absence of chromosomal rearrangements. This leads to a higher CYCLIN D1 mRNA stability, with inappropriate expression during the cell cycle. The stabilized CYCLIN D1 mRNA cooperates with TROP2 in stimulating the growth of the expressing cells. These findings show a novel epigenetic, oncogenic mechanism, which seems to be widespread in human cancers.