RNA-binding protein quaking, a critical regulator of colon epithelial differentiation and a suppressor of colon cancer.
RNA-binding protein quaking, a critical regulator of colon epithelial differentiation and a suppressor of colon cancer.
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DOI：
10.1053/j.gastro.2009.08.001
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发表时间：
2010-01
期刊：
影响因子：
29.4
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Yang G;Fu H;Zhang J;Lu X;Yu F;Jin L;Bai L;Huang B;Shen L;Feng Y;Yao L;Lu Z
从遗传学的角度来看，结肠癌是最好理解的肿瘤之一，但它仍然是癌症相关死亡的第二大常见原因。由RNA结合蛋白或microRNA介导的转录后调节协同靶向多个基因，有望参与结肠癌的发生和发展。本文研究了RNA结合蛋白QKI在结肠癌中的作用。通过RT-PCR和Western blot方法观察QKI在正常结肠和结肠癌中的表达情况。亚硫酸氢盐测序和甲基化特异性PCR用于QKI启动子甲基化分析。我们使用肠上皮细胞分化标记物和软琼脂试验来测试QKI在结肠分化和结肠癌发展中的作用。采用3 'UTR报告基因分析和RNA-IP证实QKI与β-catenin或p27之间的相互作用。QKI在某些结肠癌中表达显著下调甚至缺失，这至少部分归因于启动子的高甲基化。结肠癌细胞中强表达QKI后，肠上皮细胞分化标志物IAP和乳糖酶的表达增加，细胞周期停滞于G1期，p27 Kip 1蛋白水平升高，β-catenin膜定位增加。最后，QKI过表达降低了细胞的增殖和成瘤能力。我们的研究表明，QKI通过协同靶向与细胞生长和分化相关的多个基因，作为结肠上皮分化的主要调节因子和癌发生的抑制因子，其在结肠中的甲基化失调参与癌症的发生和发展。
Colon cancer is one of the best-understood neoplasms from a genetic perspective, yet it remains the second most common cause of cancer-related death. Post-transcriptional regulation mediated by RNA binding proteins or microRNAs coordinately targets multiple genes, holding promise involved in colon cancer initiation and development. Here we studied the role of RNA binding protein QKI in colon cancer. We observed the expression pattern of QKI in normal colon and colon cancers through RT-PCR and Western blot. Bisulfite-sequencing and methylation specific PCR were applied for QKI promoter methylation analysis. We used enterocyte differentiation markers and soft agar assay to test the role of QKI in colon differentiation and colon cancer development. 3′ UTR reporter assay and RNA-IP were used to confirm the interaction between QKI and β-catenin or p27. QKI is significantly downregulated and even absent in some colon cancers, which at least partially due to the promoter hypermethylation. Forced expression of QKI in the colon cancer cells increased the expression of enterocyte differentiation marker IAP and lactase, together with the cell cycle accumulation in G1 phase, enhancement of p27Kip1 protein level and membrane localized β-catenin. Finally, QKI overexpression reduced the proliferation and tumorigenesis ability. Our study establishes that QKI functions as a principal regulator in the differentiation of colon epithelium and a suppressor of carcinogenesis through coordinately targeting multiple genes associated with cell growth and differentiation, whose deregulation by methylation in colon is involved in cancer onset and progress.
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影响因子：
4.8
作者：
Lu, ZF;Ku, L;Feng, Y
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