E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2
E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2
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DOI：
10.1016/j.bbrc.2015.06.103
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发表时间：
2015-08-21
影响因子：
3.1
通讯作者：
Chen, Xiang
中科院分区：
文献类型：
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作者：
Fang, Zejun;Gong, Chaoju;Chen, Xiang
作为核糖核苷酸还原酶小亚基，核糖核苷酸还原酶小亚基M2 （RRM2）的高表达诱导肿瘤，促进肿瘤的生长和侵袭。在几种结直肠癌（CRC）细胞系中，我们发现RRM2的表达水平与转录因子E2F1密切相关。进行了机理研究以确定其分子基础。异位过表达E2F1促进了RRM2的转激活，而敲低E2F1则降低了RRM2 mRNA和蛋白的水平。为了进一步研究被E2F1激活的RRM2在结直肠癌中的作用，我们进行了CCK-8实验和EdU掺入实验。过表达E2F1促进CRC细胞的增殖，而这一过程被RRM2敲低抑制所阻断。在迁移和侵袭实验中，过表达E2F1可以增强CRC细胞的迁移和侵袭，而沉默RRM2则可以消除这种作用。此外，在结直肠癌细胞中，RRM2的过表达部分逆转了E2F1敲低的作用。临床CRC标本检查显示，与配对的正常组织相比，大多数癌组织中RRM2和E2F1均升高。进一步分析发现，E2F1和RRM2蛋白表达水平相互平行，且与淋巴结转移（LNM）、TNM分期及远处转移呈正相关。同样，E2F1和RRM2水平低的患者预后优于高水平的患者。因此，我们认为E2F1可能通过调控RRM2的反激活来促进结直肠癌的增殖、迁移、侵袭和转移。了解E2F1在激活RRM2转录中的作用将有助于解释E2F1和RRM2在结直肠癌中的关系，并为疾病的诊断和预后提供新的预测指标。(C) 2015爱思唯尔公司版权所有。
As the ribonucleotide reductase small subunit, the high expression of ribonucleotide reductase small subunit M2 (RRM2) induces cancer and contributes to tumor growth and invasion. In several colorectal cancer (CRC) cell lines, we found that the expression levels of RRM2 were closely related to the transcription factor E2F1. Mechanistic studies were conducted to determine the molecular basis. Ectopic overexpression of E2F1 promoted RRM2 transactivation while knockdown of E2F1 reduced the levels of RRM2 mRNA and protein. To further investigate the roles of RRM2 which was activated by E2F1 in CRC, CCK-8 assay and EdU incorporation assay were performed. Overexpression of E2F1 promoted cell proliferation in CRC cells, which was blocked by RRM2 knockdown attenuation. In the migration and invasion tests, overexpression of E2F1 enhanced the migration and invasion of CRC cells which was abrogated by silencing RRM2. Besides, overexpression of RRM2 reversed the effects of E2F1 knockdown partially in CRC cells. Examination of clinical CRC specimens demonstrated that both RRM2 and E2F1 were elevated in most cancer tissues compared to the paired normal tissues. Further analysis showed that the protein expression levels of E2F1 and RRM2 were parallel with each other and positively correlated with lymph node metastasis (LNM), TNM stage and distant metastasis. Consistently, the patients with low E2F1 and RRM2 levels have a better prognosis than those with high levels. Therefore, we suggest that E2F1 can promote CRC proliferation, migration, invasion and metastasis by regulating RRM2 transactivation. Understanding the role of E2F1 in activating RRM2 transcription will help to explain the relationship between E2F1 and RRM2 in CRC and provide a novel predictive marker for diagnosis and prognosis of the disease. (C) 2015 Elsevier Inc. All rights reserved.