Transcription factor OCT4 promotes cell cycle progression by regulating CCND1 expression in esophageal carcinoma
Transcription factor OCT4 promotes cell cycle progression by regulating CCND1 expression in esophageal carcinoma
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转录因子OCT4通过调节食管癌CCND1表达促进细胞周期进程
DOI：
10.1016/j.canlet.2014.07.049
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发表时间：
2014-11-01
期刊：
影响因子：
9.7
通讯作者：
Su, Changqing
中科院分区：
文献类型：
--
作者：
Li, Zhigang;Li, Xinxin;Su, Changqing
CCND 1基因在食管癌中过表达并加速细胞周期进程。然而，上游基因或因子直接调控CCND 1表达的机制仍不清楚。通过分析CCND 1基因的5 '-UTR区域，我们发现该区域含有八聚体基序（ATTTTGCAT），这表明CCND 1的表达可能与八聚体结合转录因子4（octamer binding transcription factor 4，OCT 4）直接相关。本研究克隆了CCND 1野生型和八聚体突变型启动子，并构建了相应的荧光素酶报告载体，以研究OCT 4调控CCND 1表达及影响食管癌细胞生物学行为的分子机制。结果表明，抑制食管癌细胞中CCND 1和OCT 4的表达可降低细胞的增殖和侵袭能力，诱导细胞周期G1期阻滞，并减缓裸鼠移植瘤的生长。抑制OCT 4表达显著降低了野生型CCND 1启动子的活性，下调了CCND 1的表达，但不影响突变型启动子的活性。然而，抑制CCND 1并不影响OCT 4的表达，这表明OCT 4通过激活CCND 1启动子并随后促进细胞周期进程来调节CCND 1的表达。结果显示并证实OCT 4是直接与CCND 1启动子结合调控CCND 1表达的上游因子，进而促进细胞周期进程，加速食管癌细胞的增殖和侵袭。这一发现可能有助于阐明食管癌细胞的细胞周期进程的调控机制，并可能有助于筛选潜在的基因靶点，用于食管癌的生物治疗。(C)2014爱思唯尔爱尔兰有限公司版权所有。
The CCND1 gene is overexpressed in esophageal cancer and accelerates cell cycle progression. However, the mechanism whereby the upstream genes or factors directly regulate CCND1 expression remains unknown. By analyzing the 5'-UTR region of the CCND1 gene, we found that this region contains an octamer motif (ATTTTGCAT), which suggests that the expression of CCND1 might be directly associated with octamer-binding transcription factor 4 (OCT4). In this study, the wild-type and the octamer motif-mutanted CCND1 promoters were cloned, and their corresponding luciferase reporter vectors were then constructed to study the molecular mechanism by which OCT4 regulates the expression of CCND1 and influences the biological behaviors of esophageal cancer cells. The results indicated that suppressing the expression of CCND1 and OCT4 in esophageal cancer cells reduced cell proliferative and invasive abilities, induced cell cycle G1-phase arrest, and slowed the growth of xenografts in nude mice. Suppression of OCT4 expression significantly decreased the wild-type CCND1 promoter activity and down-regulated the expression of CCND1, but did not affect the activity of the mutant promoter. Whereas, suppression of CCND1 did not affect OCT4 expression, suggesting that OCT4 regulates CCND1 expression by activating the CCND1 promoter and subsequently promoting cell cycle progression. The results revealed and confirmed that OCT4 is the upstream factor that directly binds to the CCND1 promoter to regulate CCND1 expression, then to promote cell cycle progression and accelerate the proliferation and invasion of esophageal cancer cells. This finding may significantly contribute to elucidating the regulatory mechanism involved in the cell cycle progression of esophageal cancer cells and may aid in screening potential gene targets for the biological therapy of esophageal cancer. (C) 2014 Elsevier Ireland Ltd. All rights reserved.