Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool.
Mutant KRAS promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool.
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DOI：
10.1053/j.gastro.2011.05.007
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发表时间：
2011-09
期刊：
影响因子：
29.4
通讯作者：
Fearon ER
中科院分区：
文献类型：
--
作者：
Feng Y;Bommer GT;Zhao J;Green M;Sands E;Zhai Y;Brown K;Burberry A;Cho KR;Fearon ER
腺瘤性息肉是结直肠癌（CRC）的前兆，而增生性息肉（HPP）进展为CRC的风险较小。在约40%的CRC和大腺瘤以及HPP的子集中发现KRAS突变。我们研究了KRAS突变的HPP缺乏恶性潜能的原因;我们比较了Kras/KRAS激活与促进腺瘤形成的腺瘤性结肠息肉病（Apc）/APC失活的影响。我们在小鼠结肠上皮中激活KrasG 12 D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和腺瘤样品验证小鼠数据。在肠上皮细胞中研究了有助于Kras/KRAS诱导表型的信号通路和因子。Kras的激活导致类似于在人类HPP中观察到的增生和锯齿状隐窝结构。我们还观察到潘氏细胞的损失和杯状细胞数量的增加。Kras介导的分化和增殖的抑制需要丝裂原活化蛋白激酶（MAPK）信号传导，并与Hes 1转录因子的激活有关。人类HPP也激活了HES 1。与Apc/APC失活相反，Kras/KRAS激活并不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 INK 4a蛋白表达的大量诱导无关。尽管Kras/KRAS突变促进结肠上皮的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信号传导不会增加受影响的隐窝中假定干细胞的数量。
Adenomatous polyps are precursors to colorectal cancer (CRC), whereas hyperplastic polyps (HPPs) have a small 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 that HPPs with KRAS mutations lack malignant potential; we compared the effects of Kras/KRAS activation to those of Adenomatous polyposis coli (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 that contribute 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 (MAPK) 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 p16INK4a protein expression in mouse colon epithelium or human HPPs. Although Kras/KRAS mutation promotes serrated and hyperplastic morphological 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.
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影响因子：
11.5
作者：
Baldus, Stephan E.;Schaefer, Karl-L.;Gabbert, Helmut E.
通讯作者：
Gabbert, Helmut E.
影响因子：
29.4
作者：
Snippert, Hugo J.;van Es, Johan H.;Clevers, Hans
通讯作者：
Clevers, Hans
影响因子：
3.1
作者：
Nishimura, S;Wakabayashi, N;Mitsufuji, S
通讯作者：
Mitsufuji, S
影响因子：
29.4
作者：
Leggett, Barbara;Whitehall, Vicki
通讯作者：
Whitehall, Vicki
DOI：
10.1083/jcb.123.4.877
发表时间：
1993-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kim SH;Roth KA;Moser AR;Gordon JI
通讯作者：
Gordon JI