Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Cancer Discov. 2011 Jun;1(1):35-43. doi: 10.1158/2159-8274.CD-10-0022. Epub 2011 Jun 1.
Using an integrative genomics approach called amplification breakpoint ranking and assembly analysis, we nominated KRAS as a gene fusion with the ubiquitin-conjugating enzyme UBE2L3 in the DU145 cell line, originally derived from prostate cancer metastasis to the brain. Interestingly, analysis of tissues revealed that 2 of 62 metastatic prostate cancers harbored aberrations at the KRAS locus. In DU145 cells, UBE2L3-KRAS produces a fusion protein, a specific knockdown of which attenuates cell invasion and xenograft growth. Ectopic expression of the UBE2L3-KRAS fusion protein exhibits transforming activity in NIH 3T3 fibroblasts and RWPE prostate epithelial cells in vitro and in vivo. In NIH 3T3 cells, UBE2L3-KRAS attenuates MEK/ERK signaling, commonly engaged by oncogenic mutant KRAS, and instead signals via AKT and p38 mitogen-activated protein kinase (MAPK) pathways. This is the first report of a gene fusion involving the Ras family, suggesting that this aberration may drive metastatic progression in a rare subset of prostate cancers.
This is the first description of an oncogenic gene fusion of KRAS, one of the most studied proto-oncogenes. KRAS rearrangement may represent the driving mutation in a rare subset of metastatic prostate cancers, emphasizing the importance of RAS-RAF-MAPK signaling in this disease.
使用一种称为扩增断点排名和组装分析的综合基因组学方法，我们提名 KRAS 为与泛素连接酶 UBE2L3 的基因融合，该基因融合最初源自前列腺癌转移到大脑的 DU145 细胞系。有趣的是，对组织的分析表明，62 例转移性前列腺癌中有 2 例存在 KRAS 基因座的异常。在 DU145 细胞中，UBE2L3-KRAS 产生融合蛋白，其特异性敲低可减弱细胞侵袭和异种移植物生长。UBE2L3-KRAS 融合蛋白的异位表达在体外和体内具有 NIH 3T3 成纤维细胞和 RWPE 前列腺上皮细胞的转化活性。在 NIH 3T3 细胞中，UBE2L3-KRAS 减弱了通常由致癌性突变 KRAS 参与的 MEK/ERK 信号传导，而是通过 AKT 和 p38 丝裂原活化蛋白激酶 (MAPK) 途径发出信号。这是第一个涉及 Ras 家族的基因融合报告，表明这种异常可能在少数前列腺癌转移中驱动转移进展。
这是对最具研究价值的原癌基因之一 KRAS 的致癌基因融合的首次描述。KRAS 重排可能代表少数转移性前列腺癌中驱动突变，强调 RAS-RAF-MAPK 信号在该疾病中的重要性。
