Colorectal cancer (CRC) tumorigenesis and progression are linked to common oncogenic mutations, especially in the tumor suppressor APC, whose loss triggers the deregulation of TCF4/β-Catenin activity. CRC tumorigenesis is also driven by multiple epi-mutational modifiers, such as transcriptional regulators. We describe the common (and near-universal) activation of the zinc finger transcription factor and Let-7 target PLAGL2 in CRC and find that it is a key driver of intestinal epithelial transformation. PLAGL2 drives proliferation, cell cycle progression, and anchorage-independent growth in CRC cell lines and non-transformed intestinal cells. Investigating effects of PLAGL2 on downstream pathways revealed very modest effects on canonical Wnt signaling. Alternatively, we find pronounced effects on the direct PLAGL2 target genes IGF2, a fetal growth factor, and ASCL2, an intestinal stem cell-specific bHLH transcription factor. Inactivation of PLAGL2 in CRC cell lines has pronounced effects on ASCL2 reporter activity. Furthermore, ASCL2 expression can partially rescue deficits of proliferation and cell cycle progression caused by depletion of PLAGL2 in CRC cell lines. Thus, the oncogenic effects of PLAGL2 appear to be mediated via core stem cell and onco-fetal pathways, with minimal effects on downstream Wnt signaling.

中文翻译：

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PLAGL2 的致癌功能是通过特定靶基因通过 Wnt 非依赖性机制在结直肠癌中介导的

结直肠癌 (CRC) 的肿瘤发生和进展与常见的致癌突变有关，尤其是在肿瘤抑制基因APC中，其丢失触发 TCF4/β-连环蛋白活性的失调。CRC 肿瘤发生也由多种表观突变修饰剂驱动，例如转录调节剂。我们描述了 CRC 中锌指转录因子和 Let-7 靶向 PLAGL2 的常见（和近乎普遍）激活，并发现它是肠上皮转化的关键驱动因素。PLAGL2 驱动 CRC 细胞系和非转化肠细胞的增殖、细胞周期进程和不依赖锚定的生长。研究 PLAGL2 对下游通路的影响揭示了对经典 Wnt 信号传导的非常温和的影响。或者，我们发现对直接 PLAGL2 靶基因IGF2、胎儿生长因子和ASCL2有显着影响，一种肠道干细胞特异性 bHLH 转录因子。CRC 细胞系中 PLAGL2 的失活对 ASCL2 报告基因的活性有显着影响。此外，ASCL2 表达可以部分挽救由 CRC 细胞系中 PLAGL2 耗竭引起的增殖和细胞周期进程的缺陷。因此，PLAGL2 的致癌作用似乎是通过核心干细胞和癌胎途径介导的，对下游 Wnt 信号传导的影响最小。