Down-regulation of cIAP2 enhances 5-FU sensitivity through the apoptotic pathway in human colon cancer cells
Down-regulation of cIAP2 enhances 5-FU sensitivity through the apoptotic pathway in human colon cancer cells
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DOI：
10.1111/j.1349-7006.2009.01112.x
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发表时间：
2009-05-01
期刊：
影响因子：
5.7
通讯作者：
Sasaki, Iwao
中科院分区：
文献类型：
--
作者：
Karasawa, Hideaki;Miura, Koh;Sasaki, Iwao
目前，5-氟尿嘧啶（5-FU）在结直肠癌的化疗方案中起着核心作用，因此了解决定5-FU敏感性的机制非常重要。比较人结肠癌细胞系DLD-1及其5-FU耐药亚克隆DLD-1/FU和另外21种结肠癌细胞系的表达谱，以鉴定决定5-FU敏感性的新基因，并估计哪些基因群体负责5-FU敏感性。在系统聚类中，尽管DLD-1和DLD-1/FU对5-FU的50%抑制浓度相差超过100倍，但DLD-1和DLD-1/FU聚类最紧密。在DLD-1/FU中，与DLD-1相比差异表达的基因群体限于3.3%，尽管在其他21个细胞系中其范围为4.8%至24.0%，因此表明5-FU敏感性的差异由有限数量的基因定义。接下来，使用RNA干扰研究了细胞凋亡抑制因子2（cIAP 2）基因（在DLD-1/FU中上调）对5-FU耐药性的作用。下调cIAP 2可有效增强5-FU敏感性、caspase 3/7激活和5-FU诱导的细胞凋亡。对III期结直肠癌患者癌组织和相应正常组织中cIAP 2的免疫组化结果显示，cIAP 2在癌组织中的表达频率高于正常组织，且cIAP 2阳性患者在氟尿嘧啶化疗后有早期复发的趋势。虽然药物敏感性和IAP家族在结直肠癌中的关系尚未讨论，但cIAP 2可能因此在结直肠癌中作为靶向治疗发挥重要作用。（Cancer Sci 2009; 100：903-913）。
Currently 5-fluorouracil (5-FU) plays a central role in the chemotherapeutic regimens for colorectal cancers and thus it is important to understand the mechanisms that determine 5-FU sensitivity. The expression profiles of human colon cancer cell line DLD-1, its 5-FU-resistant subclone DLD-1/FU and a futher 21 types of colon cancer cell lines were compared to identify the novel genes defining the sensitivity to 5-FU and to estimate which population of genes is responsible for 5-FU sensitivity. In the hierarchical clustering, DLD-1 and DLD-1/FU were most closely clustered despite over 100 times difference in their 50% inhibitory concentration of 5-FU. In DLD-1/FU, the population of genes differentially expressed compared to DLD-1 was limited to 3.3%, although it ranged from 4.8% to 24.0% in the other 21 cell lines, thus indicating that the difference of 5-FU sensitivity was defined by a limited number of genes. Next, the role of the cellular inhibitor of apoptosis 2 (cIAP2) gene, which was up-regulated in DLD-1/FU, was investigated for 5-FU resistance using RNA interference. The down-regulation of cIAP2 efficiently enhanced 5-FU sensitivity, the activation of caspase 3/7 and apoptosis under exposure to 5-FU. The immunohistochemistry of cIAP2 in cancer and corresponding normal tissues from colorectal cancer patients in stage III revealed that cIAP2 was more frequently expressed in cancer tissues than in normal tissues, and cIAP2-positive patients had a trend toward early recurrence after fluorouracil-based chemotherapy. Although the association between drug sensitivity and the IAP family in colorectal cancer has not yet been discussed, cIAP2 may therefore play an important role as a target therapy in colorectal cancer. (Cancer Sci 2009; 100: 903-913).