Division of Molecular Medicine & Genetics, Departments of Internal Medicine, Human Genetics, and Pathology, and the Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Gastroenterology. 2011 Sep;141(3):1003-1013.e1-10. doi: 10.1053/j.gastro.2011.05.007. Epub 2011 May 18.
BACKGROUND & AIMS: Adenomatous polyps are precursors to colorectal cancer (CRC), whereas hyperplastic polyps (HPPs) have low risk of progression to CRC. Mutations in KRAS are found in ∼40% of CRCs and large adenomas and a subset of HPPs. We investigated the reasons why HPPs with KRAS mutations lack malignant potential and compared the effects of Kras/KRAS activation with those of Apc/APC inactivation, which promotes adenoma formation.
We activated a KrasG12D mutant allele or inactivated Apc alleles in mouse colon epithelium and analyzed phenotypes and expression of selected genes and proteins. The mouse data were validated using samples of human HPPs and adenomas. Signaling pathways and factors contributing to Kras/KRAS-induced phenotypes were studied in intestinal epithelial cells.
Activation of Kras led to hyperplasia and serrated crypt architecture akin to that observed in human HPPs. We also observed loss of Paneth cells and increases in goblet cell numbers. Abnormalities in Kras-mediated differentiation and proliferation required mitogen-activated protein kinase signaling and were linked to activation of the Hes1 transcription factor. Human HPPs also had activation of HES1. In contrast to Apc/APC inactivation, Kras/KRAS activation did not increase expression of crypt stem cell markers in colon epithelium or colony formation in vitro. Kras/KRAS activation was not associated with substantial induction of p16(INK4a) protein expression in mouse colon epithelium or human HPPs.
Although Kras/KRAS mutation promotes serrated and hyperplastic morphologic features in colon epithelium, it is not able to initiate adenoma development, perhaps in part because activated Kras/KRAS signaling does not increase the number of presumptive stem cells in affected crypts.
腺瘤性息肉是结直肠癌（CRC）的前体，而增生性息肉（HPP）进展为 CRC 的风险较低。KRAS 突变存在于约 40%的 CRC 和大型腺瘤以及一部分 HPP 中。我们研究了为什么带有 KRAS 突变的 HPP 缺乏恶性潜能，并比较了 Kras/KRAS 激活与促进腺瘤形成的 Apc/APC 失活的影响。
我们在小鼠结肠上皮中激活 KrasG12D 突变等位基因或失活 Apc 等位基因，并分析选定基因和蛋白质的表型和表达。使用人 HPP 和腺瘤样本验证了小鼠数据。研究了在肠上皮细胞中导致 Kras/KRAS 诱导表型的信号通路和因素。
Kras 的激活导致增生和锯齿状隐窝结构，类似于人 HPP 中观察到的结构。我们还观察到 Paneth 细胞丢失和杯状细胞数量增加。Kras 介导的分化和增殖异常需要丝裂原活化蛋白激酶信号，并与 Hes1 转录因子的激活有关。人 HPP 中也有 HES1 的激活。与 Apc/APC 失活相反，Kras/KRAS 激活不会增加结肠上皮中隐窝干细胞标志物的表达或体外集落形成。Kras/KRAS 激活与小鼠结肠上皮或人 HPP 中 p16(INK4a)蛋白表达的大量诱导无关。
尽管 Kras/KRAS 突变促进结肠上皮中锯齿状和增生性形态特征，但它不能启动腺瘤的发展，部分原因可能是激活的 Kras/KRAS 信号不会增加受影响隐窝中假定的干细胞数量。
