Loss of function of the candidate tumor suppressor prox1 by RNA mutation in human cancer cells
Loss of function of the candidate tumor suppressor prox1 by RNA mutation in human cancer cells
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DOI：
10.1593/neo.06595
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发表时间：
2006-12-01
期刊：
影响因子：
4.8
通讯作者：
Kubo, Hajime
中科院分区：
文献类型：
--
作者：
Takahashi, Meiko;Yoshimoto, Takanobu;Kubo, Hajime
人们已经认识到基因突变在肿瘤发生中的重要性，并提出mRNA的异常突变可能代表一种新的致癌原理。在这里，我们报道了同源框基因PROX1的mRNA，一个候选的肿瘤抑制基因，经历了腺苷到肌苷的核苷酸转换，并在人类癌症的一个子集中失去了肿瘤抑制功能。Prox1在胰腺癌中的表达降低，其降低程度与肿瘤的分化程度有关。从人癌细胞中提取的PROX1基因的A-to-G碱基发生了改变，而相应的基因组DNA中却没有。我们定位了PROX1基因的四个常见突变位点，并在几种癌症的临床标本中发现了相同的四个突变位点。四环素诱导的野生型Prox1抑制肿瘤细胞的转化活性和细胞增殖。然而，四个共同位点从A改变为G的突变体Prox1失去了这些抑制功能。在小鼠中，带有四环素诱导的wt-Prox1的肿瘤细胞异种移植形成肿瘤块的速度明显慢于对照肿瘤，而突变的Prox1没有任何影响。这些发现可能表明PROX1基因的RNA突变在人类癌症进展的发病机制中起着关键作用。
The importance of genetic mutations in carcinogenesis has been recognized, and it has been proposed that aberrant mutation of mRNA may represent a novel oncogenic principle. Here we report that the mRNA of a homeobox gene prox1, a candidate tumor suppressor, suffers adenosine-to-inosine nucleotide conversion and loses tumor-suppressive functions in a subset of human cancers. Expression of Prox1 was reduced in pancreatic cancers, and the extent of reduction correlated with progression of tumor differentiation. A-to-G base change was found in prox1 cDNA taken from human cancer cells, but not in corresponding genomic DNA. We mapped four common mutation sites in prox1 gene, and the same four sites were mutated in human clinical samples from several cancers. Tetracycline-induced wild-type (wt) Prox1 in tumor cells inhibited transforming activity and cellular proliferation. However, mutant Prox1 with the four common sites altered from A to G lost these inhibitory functions. In mice, xenografts of tumor cells with tetracycline-induced wt-Prox1 formed tumor masses significantly more slowly than control tumors, whereas mutated Prox1 had no effect. These findings may point to a pivotal role of the RNA mutation of prox1 gene in the pathogenesis of human cancer progression.