Ghaleb Amr M, Elkarim Enas A, Bialkowska Agnieszka B, Yang Vincent W
Department of Medicine, Stony Brook University, Stony Brook, New York.
Department of Medicine, Stony Brook University, Stony Brook, New York. Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York.
Mol Cancer Res. 2016 Apr;14(4):385-96. doi: 10.1158/1541-7786.MCR-15-0410. Epub 2016 Feb 2.
The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently downregulated in colorectal cancer. Previous studies showed that KLF4 is a tumor suppressor in the intestinal tract and plays an important role in DNA damage-repair mechanisms. Here, the in vivo effects of Klf4 deletion were examined from the mouse intestinal epithelium (Klf4(ΔIS)) in a genetic or pharmacological setting of colonic tumorigenesis:Apc(Min/⁺) mutation or carcinogen treatment with azoxymethane (AOM), respectively.Klf4 (ΔIS)/Apc (Min/⁺) mice developed significantly more colonic adenomas with 100% penetrance as compared with Apc(Min/⁺) mice with intact Klf4 (Klf4(fl/fl)/Apc (Min/⁺)). The colonic epithelium of Klf4 (ΔIS)/Apc (Min/⁺)mice showed increased mTOR pathway activity, together with dysregulated epigenetic mechanism as indicated by altered expression of HDAC1 and p300. Colonic adenomas from both genotypes stained positive for γH2AX, indicating DNA double-strand breaks. InKlf4 (ΔIS)/Apc (Min/+) mice, this was associated with reduced nonhomologous end joining (NHEJ) repair and homologous recombination repair (HRR) mechanisms as indicated by reduced Ku70 and Rad51 staining, respectively. In a separate model, following treatment with AOM, Klf4 (ΔIS) mice developed significantly more colonic tumors than Klf4 (fl/fl) mice, with more Klf4 (ΔIS) mice harboring K-Rasmutations than Klf4 (fl/fl)mice. Compared with AOM-treated Klf4 (fl/fl)mice, adenomas of treated Klf4 (ΔIS) mice had suppressed NHEJ and HRR mechanisms, as indicated by reduced Ku70 and Rad51 staining. This study highlights the important role of KLF4 in suppressing the development of colonic neoplasia under different tumor-promoting conditions.
The study demonstrates that KLF4 plays a significant role in the pathogenesis of colorectal neoplasia.
锌指转录因子Krüppel样因子4（KLF4）在结直肠癌中经常下调。先前的研究表明，KLF4是肠道中的肿瘤抑制因子，在DNA损伤修复机制中起重要作用。在此，在结肠肿瘤发生的遗传或药理学背景下，从小鼠肠道上皮（Klf4(ΔIS)）研究Klf4缺失的体内效应：分别为Apc(Min/⁺)突变或用偶氮甲烷（AOM）进行致癌物处理。与具有完整Klf4的Apc(Min/⁺)小鼠（Klf4(fl/fl)/Apc(Min/⁺)）相比，Klf4(ΔIS)/Apc(Min/⁺)小鼠发生的结肠腺瘤明显更多，且发生率为100%。Klf4(ΔIS)/Apc(Min/⁺)小鼠的结肠上皮显示mTOR通路活性增加，同时表观遗传机制失调，如HDAC1和p300表达改变所示。两种基因型的结肠腺瘤γH2AX染色均为阳性，表明存在DNA双链断裂。在Klf4(ΔIS)/Apc(Min/+)小鼠中，这分别与Ku70和Rad51染色减少所表明的非同源末端连接（NHEJ）修复和同源重组修复（HRR）机制降低有关。在另一个模型中，用AOM处理后，Klf4(ΔIS)小鼠发生的结肠肿瘤明显多于Klf(fl/fl)小鼠，携带K-Ras突变的Klf4(ΔIS)小鼠比Klf(fl/fl)小鼠更多。与经AOM处理的Klf(fl/fl)小鼠相比，经处理的Klf4(ΔIS)小鼠的腺瘤NHEJ和HRR机制受到抑制，如Ku70和Rad51染色减少所示。本研究强调了KLF4在不同肿瘤促进条件下抑制结肠肿瘤形成中的重要作用。
该研究表明KLF4在结直肠肿瘤的发病机制中起重要作用。
