Decreased Expression of the RAS-GTPase Activating Protein RASAL1 Is Associated With Colorectal Tumor Progression
Decreased Expression of the RAS-GTPase Activating Protein RASAL1 Is Associated With Colorectal Tumor Progression
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DOI：
10.1053/j.gastro.2008.09.063
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发表时间：
2009-01-01
期刊：
影响因子：
29.4
通讯作者：
Omata, Masao
中科院分区：
文献类型：
--
作者：
Ohta, Miki;Seto, Motoko;Omata, Masao
背景和目标：虽然结直肠癌（CRC）进展与KRAS和RAS信号的改变有关，但并非所有CRC细胞都有KRAS基因突变。RAS活性受RAS-GTP酶激活蛋白（RASGAP）调节，因此我们研究了RASGAP在CRC进展中的作用。方法：采用实时荧光定量聚合酶链反应（RT-PCR）检测RASGAP在大肠癌细胞中的表达水平。应用免疫组织化学方法检测RAS蛋白激活物样1（RASAL 1）在临床大肠肿瘤中的表达。研究了可能影响RASAL 1表达的临床病理（年龄、性别、肿瘤部位和分级）和分子（KRAS基因突变、CTNNB 1和TP 53表达模式）因素。结果如下：在检查的12种RASGAP中，CRC细胞中仅RASAL 1的表达水平下降; RASAL 1在大多数具有野生型KRAS基因的CRC细胞中表达下降，但在具有突变型KRAS基因的CRC细胞中表达很少。转染试验表明，RASAL 1抑制RAS/丝裂原活化蛋白激酶信号，以响应生长因子刺激，并减少含有野生型KRAS基因的CRC细胞的增殖。RASAL 1在腺癌中的表达率为46.9%（30/64），在大腺瘤中的表达率为17.4%（8/46），小腺瘤中无表达（0/42）。RASAL 1表达水平与CRC肿瘤样本中野生型KRAS基因的存在（P = 0.0010）、远端位置（P = 0.0066）和TP 53的异常表达（P = 0.0208）相关。结论：RASAL 1在含有野生型KRAS基因的结直肠癌细胞中表达降低。RASAL 1表达的减少在晚期病变中比在小腺瘤中更频繁地检测到，这表明RASAL 1在良性结肠肿瘤的进展中起作用。
Background & Aims: Although colorectal cancer (CRC) progression has been associated with alterations in KRAS and RAS signaling, not all CRC cells have KRAS gene mutations. RAS activity is modulated by RAS-GTPase-activating proteins (RASGAPs), so we investigated the role of RASGAPs in CRC progression. Methods: The level of RASGAP expression in CRC cells was analyzed using quantitative real-time polymerase chain reaction. The expression of the RAS protein activator like-1 (RASAL1) was examined in clinical colorectal neoplasms using immunohistochemistry. The clinicopathologic (age, sex, and tumor site and grade) and molecular (KRAS gene mutation, as well as CTNNB1 and TP53 expression patterns) factors that could affect RASAL1 expression were examined. Results: Of 12 RASGAPs examined, expression levels of only RASAL1 decreased in CRC cells; RASAL1 expression decreased in most CRC cells with wild-type KRAS gene but rarely in those with mutant KRAS gene. A transfection assay showed that RASAL1 repressed RAS/mitogen-activated protein kinase signaling in response to growth factor stimulation and reduced proliferation of CRC cells that contained wild-type KRAS gene. RASAL1 expression was detected in 46.9% (30/64) of adenocarcinoma, 17.4% (8/46) of large adenoma, and no (0/42) small adenoma samples. RASAL1 expression levels were correlated with the presence of wild-type KRAS gene in CRC tumor samples (P = .0010), distal location (P = .0066), and abnormal expression of TP53 (P = .0208). Conclusions: RASAL1 expression is reduced in CRC cells that contain wild-type KRAS gene. Reductions in RASAL1 expression were detected more frequently in advanced lesions than in small adenomas, suggesting that RASAL1 functions in the progression of benign colonic neoplasms.