Aberrant activation of hedgehog signaling promotes cell proliferation via the transcriptional activation of forkhead Box M1 in colorectal cancer cells.
Aberrant activation of hedgehog signaling promotes cell proliferation via the transcriptional activation of forkhead Box M1 in colorectal cancer cells.
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在结直肠癌细胞中，hedgehog信号传导的异常激活通过叉头盒M1的转录激活促进细胞增殖
DOI：
10.1186/s13046-017-0491-7
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发表时间：
2017-02-02
期刊：
影响因子：
--
通讯作者：
Luo S
中科院分区：
文献类型：
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作者：
Wang D;Hu G;Du Y;Zhang C;Lu Q;Lv N;Luo S
最近的证据表明，Gli 转录因子异常激活 Hedgehog (Hh) 信号是多种侵袭性人类癌症的特征，包括结直肠癌 (CRC)。叉头盒 M1 (FoxM1) 控制许多细胞周期调节蛋白的表达，并且 FoxM1 表达在多种人类恶性肿瘤中升高，这表明它在肿瘤发生中发挥着至关重要的作用。然而，FoxM1 表达的机制尚不完全清楚。在这里，我们的目的是进一步研究Gli1在结直肠癌中调节FoxM1的分子机制。使用蛋白质印迹和免疫组织化学 (IHC) 分别评估 CRC 组织和匹配的邻近正常粘膜中的 FoxM1 和 Gli1 蛋白表达。使用 BrdU（5-溴-2'-脱氧尿苷）和克隆形成测定来阐明 FoxM1 对 CRC 细胞生长和增殖的影响。进行染色质免疫沉淀 (ChIP) 和荧光素酶实验来探索 Gli1 调节 FoxM1 的潜在机制。此外，使用蛋白质印迹和实时 PCR 测量了六种 CRC 细胞系中 Gli1 和 FoxM1 的蛋白和 mRNA 表达水平。最后，在细胞生物学实验中研究了Hh信号对FoxM1表达的影响，并通过流式细胞术评估了Hh信号激活和FoxM1抑制对CRC细胞在细胞周期时相分布的影响。与匹配的邻近正常粘膜样本相比，Gli1和FoxM1在人结直肠癌组织中异常升高，并且FoxM1是结直肠癌中转录因子Gli1的下游靶基因，促进结直肠癌细胞的生长和增殖。此外，Hh信号的异常激活通过直接结合FoxM1的启动子并反式激活CRC细胞中FoxM1的活性来促进CRC细胞增殖。 Hh-Gli1-FoxM1 轴的失调对于人类 CRC 细胞的增殖和生长至关重要，并为 CRC 的治疗干预提供了有效的靶点。本文的在线版本 (doi:10.1186/s13046-017-0491-7) 包含补充材料，可供授权用户使用。
Recent evidence suggests that the aberrant activation of Hedgehog (Hh) signaling by Gli transcription factors is characteristic of a variety of aggressive human carcinomas, including colorectal cancer (CRC). Forkhead box M1 (FoxM1) controls the expression of a number of cell cycle regulatory proteins, and FoxM1 expression is elevated in a broad range of human malignancies, which suggests that it plays a crucial role in tumorigenesis. However, the mechanisms underlying FoxM1 expression are not fully understood. Here, we aim to further investigate the molecular mechanism by which Gli1 regulates FoxM1 in CRC. Western blotting and immunohistochemistry (IHC) were used to evaluate FoxM1 and Gli1 protein expression, respectively, in CRC tissues and matched adjacent normal mucosa. BrdU (5-bromo-2′-deoxyuridine) and clone formation assays were used to clarify the influence of FoxM1 on CRC cell growth and proliferation. Chromatin immunoprecipitation (ChIP) and luciferase experiments were performed to explore the potential mechanisms by which Gli1 regulates FoxM1. Additionally, the protein and mRNA expression levels of Gli1 and FoxM1 in six CRC cell lines were measured using Western blotting and real-time PCR. Finally, the effect of Hh signaling on the expression of FoxM1 was studied in cell biology experiments, and the effects of Hh signaling activation and FoxM1 inhibition on the distribution of CRC cells among cell cycle phases was assessed by flow cytometry. Gli1 and FoxM1 were abnormally elevated in human CRC tissues compared with matched adjacent normal mucosa samples, and FoxM1 is a downstream target gene of the transcription factor Gli1 in CRC and promoted CRC cell growth and proliferation. Moreover, the aberrant activation of Hh signaling promoted CRC cell proliferation by directly binding to the promoter of FoxM1 and transactivating the activity of FoxM1 in CRC cells. The dysregulation of the Hh-Gli1-FoxM1 axis is essential for the proliferation and growth of human CRC cells and offers a potent target for therapeutic intervention in CRC. The online version of this article (doi:10.1186/s13046-017-0491-7) contains supplementary material, which is available to authorized users.