Loss of the nuclear Wnt pathway effector TCF7L2 promotes migration and invasion of human colorectal cancer cells
Loss of the nuclear Wnt pathway effector TCF7L2 promotes migration and invasion of human colorectal cancer cells
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DOI：
10.1038/s41388-020-1259-7
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发表时间：
2020-03-20
期刊：
影响因子：
8
通讯作者：
Hecht, Andreas
中科院分区：
文献类型：
--
作者：
Wenzel, Janna;Rose, Katja;Hecht, Andreas
转录因子TCF 7 L2对于肠组织稳态是必不可少的，其中它在干细胞和祖细胞中传递促有丝分裂Wnt/β-连环蛋白信号，肠肿瘤由此产生。然而，TCF 7 L2属于结直肠癌（CRC）中最频繁突变的基因，并且提出了TCF 7 L2的肿瘤抑制功能。这一明显的矛盾需要阐明TCF 7 L2在结直肠癌发生中的作用。在这里，我们研究了CRC细胞的TCF 7 L2依赖性/不依赖性以及TCF 7 L2功能丧失的细胞和分子后果。通过基因组编辑，我们在几种CRC细胞系中实现了TCF 7 L2的完全失活，而没有丧失活力，这表明CRC细胞已经广泛失去了对TCF 7 L2的严格要求。TCF 7 L2缺陷损害G1/S进展，这让人想起TCF 7 L2的生理作用。此外，TCF 7 L2阴性细胞表现出形态学变化，增强迁移，侵袭和胶原粘附，尽管表型改变的严重程度表现在细胞系特异性的方式。为了为观察到的细胞变化提供分子框架，我们进行了全球转录组分析，并确定了基因调控网络，其中TCF 7 L2正调控原癌基因MYC，同时抑制细胞周期抑制剂CDKN 2C/CDKN 2D。与其抑制细胞运动和侵袭的功能一致，TCF 7 L2直接抑制促转移转录因子RUNX 2并影响细胞粘附分子的表达。总之，我们得出结论，TCF 7 L2的增殖刺激活性持续在CRC细胞。此外，TCF 7 L2还具有侵袭抑制作用。尽管TCF 7 L2对细胞周期进程有负面影响，但其功能丧失可能因此增加恶性程度，这可以解释为什么TCF 7 L2在相当大比例的结直肠肿瘤中发生突变。
The transcription factor TCF7L2 is indispensable for intestinal tissue homeostasis where it transmits mitogenic Wnt/beta-Catenin signals in stem and progenitor cells, from which intestinal tumors arise. Yet, TCF7L2 belongs to the most frequently mutated genes in colorectal cancer (CRC), and tumor-suppressive functions of TCF7L2 were proposed. This apparent paradox warrants to clarify the role of TCF7L2 in colorectal carcinogenesis. Here, we investigated TCF7L2 dependence/independence of CRC cells and the cellular and molecular consequences of TCF7L2 loss-of-function. By genome editing we achieved complete TCF7L2 inactivation in several CRC cell lines without loss of viability, showing that CRC cells have widely lost the strict requirement for TCF7L2. TCF7L2 deficiency impaired G1/S progression, reminiscent of the physiological role of TCF7L2. In addition, TCF7L2-negative cells exhibited morphological changes, enhanced migration, invasion, and collagen adhesion, albeit the severity of the phenotypic alterations manifested in a cell-line-specific fashion. To provide a molecular framework for the observed cellular changes, we performed global transcriptome profiling and identified gene-regulatory networks in which TCF7L2 positively regulates the proto-oncogene MYC, while repressing the cell cycle inhibitors CDKN2C/CDKN2D. Consistent with its function in curbing cell motility and invasion, TCF7L2 directly suppresses the pro-metastatic transcription factor RUNX2 and impinges on the expression of cell adhesion molecules. Altogether, we conclude that the proliferation-stimulating activity of TCF7L2 persists in CRC cells. In addition, TCF7L2 acts as invasion suppressor. Despite its negative impact on cell cycle progression, TCF7L2 loss-of-function may thereby increase malignancy, which could explain why TCF7L2 is mutated in a sizeable fraction of colorectal tumors.