Loss of FBXW7, a cell cycle regulating gene, in colorectal cancer: clinical significance
Loss of FBXW7, a cell cycle regulating gene, in colorectal cancer: clinical significance
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DOI：
10.1002/ijc.24879
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发表时间：
2010-04-15
影响因子：
6.4
通讯作者：
Mori, Masaki
中科院分区：
文献类型：
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作者：
Iwatsuki, Masaaki;Mimori, Koshi;Mori, Masaki
本研究的重点是细胞周期调控基因FBXW 7，它泛素化c-Myc和细胞周期蛋白E，并促进退出细胞周期。我们确定了FBXW 7在结直肠癌（CRC）病例中的表达水平，将这些值与临床病理特征相关联，并表征了体外CRC细胞中FBXW 7表达降低的分子机制。检测93例大肠癌组织中FBXW 7 mRNA和蛋白的表达。用CGH芯片检测130例大肠癌组织中FBXW 7基因侧翼区的拷贝数畸变。进行CRC细胞中FBXW 7基因沉默的体外分析。FBXW 7 mRNA在肿瘤组织中的表达明显低于相应的正常组织。FBXW 7低表达组患者的预后明显差于高表达组患者。FBXW 7阻遏的发生率和遗传改变之间观察到一致的关系。基因改变的发生率与疾病进展的阶段有关。在体外，FBXW 7特异性siRNA增强c-MYC和细胞周期蛋白E蛋白的表达，并上调细胞增殖。肿瘤中的遗传改变导致FBXW 7表达的丧失和细胞增殖的增加。FBXW 7表达为CRC患者提供了一个预后因子。
This study focused on a cell cycle regulatory gene, FBXW7, which ubiquitinates c-Myc and cyclin E and promotes exit from the cell cycle. We determined the expression level of FBXW7 in colorectal cancer (CRC) cases, correlated those values with clinicopathologic features, and characterized the molecular mechanism of reduced expression of FBXW7 in CRC cells in vitro. FBXW7 mRNA and protein expression were evaluated in 93 CRC cases. Using CGH array, the copy number aberrations of the flanking region of FBXW7 were evaluated in another 130 CRC specimens. In vitro analysis of FBXW7 gene silencing in CRC cells was conducted. FBXW7 mRNA expression was significantly lower in tumor tissues than the corresponding normal tissues. The low FBXW7 expression group showed a significantly poorer prognosis than patients in the high expression group. A concordant relationship was observed between the incidence of FBXW7 repression and the genetic alteration. The incidence of genetic alteration was associated with the stage of disease progression. In vitro, FBXW7-specific siRNA enhanced expression of c-MYC and cyclin E proteins and up-regulated cell proliferation. Genetic alterations in tumors led to the loss of FBXW7 expression and increased cell proliferation. FBXW7 expression provides a prognostic factor for patients with CRC.