Zhang Yafei, Zhang Anran, Shen Caifei, Zhang Bicheng, Rao Zhiguo, Wang Rongquan, Yang Shiming, Ning Shoubin, Mao Gaoping, Fang Dianchun
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China.
Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army, Wuhan, P.R. China.
Oncol Rep. 2014 Sep;32(3):1273-80. doi: 10.3892/or.2014.3287. Epub 2014 Jun 24.
Since induction of hTERT expression and subsequent telomerase activation play a critical role in the multistep process of tumorigenesis, a better understanding of hTERT regulation may provide not only a rationale for the molecular basis of cancer progression but also a path to the development of cancer prevention. The c-Myc oncoprotein can function effectively in activating the transcriptional expression of hTERT through E-box elements on its promoter. E2F transcription factor 1 (E2F1) was found to be a repressor of hTERT transcription by directly binding to its promoter, thereby inhibiting hTERT protein expression. For the extensively crosstalk between c-Myc and E2F1 signals, which is now known to be vital to cell fate, we speculated that E2F1 may play a negative regulatory role in c-Myc-induced hTERT transcription. In the present study, we chose to use human embryonic fibroblast cells as an experimental model system, and present evidence that the E2F1 transcription factor constitutes a negative regulatory system to limit c-Myc transcriptional activation of hTERT in normal cells. Furthermore, we demonstrated that upregulation of the miR-17-92 cluster (miR-20a/miR-17-5p) is involved in the regulation of E2F1-mediated negative feedback of the c-Myc/hTERT pathway. Our results not only reveal novel insights into how normal cells control the transmission of c-Myc-mediated oncogenic signals, but also further establish E2F1 as an important molecular target for cancer therapy.
由于hTERT表达的诱导及随后的端粒酶激活在肿瘤发生的多步骤过程中起关键作用，更好地理解hTERT调控不仅可为癌症进展的分子基础提供理论依据，还可为癌症预防的发展提供途径。c-Myc癌蛋白可通过其启动子上的E-box元件有效激活hTERT的转录表达。发现E2F转录因子1（E2F1）通过直接结合hTERT启动子而成为其转录的抑制因子，从而抑制hTERT蛋白表达。鉴于c-Myc和E2F1信号之间广泛的相互作用（现已知道这对细胞命运至关重要），我们推测E2F1可能在c-Myc诱导的hTERT转录中起负调控作用。在本研究中，我们选择使用人胚胎成纤维细胞作为实验模型系统，并提供证据表明E2F1转录因子构成一个负调控系统，以限制正常细胞中c-Myc对hTERT的转录激活。此外，我们证明miR-17-92簇（miR-20a/miR-17-5p）的上调参与了E2F1介导的c-Myc/hTERT途径负反馈的调控。我们的结果不仅揭示了正常细胞如何控制c-Myc介导的致癌信号传递的新见解，还进一步确立了E2F1作为癌症治疗的重要分子靶点。
