KLF4 inhibits colorectal cancer cell proliferation dependent on NDRG2 signaling
KLF4 inhibits colorectal cancer cell proliferation dependent on NDRG2 signaling
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KLF4 依赖 NDRG2 信号传导抑制结直肠癌细胞增殖
DOI：
10.3892/or.2017.5736
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发表时间：
2017-08-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Ma, Yongzheng;Wu, Lin;Zhang, Jian
Kruppel-like factor4(KLF4)是一种锌指转录因子，已被证实是结直肠癌的抑癌基因。KLF4通过上调p21(WAF1/Cip1)和下调细胞周期蛋白D1抑制结直肠癌细胞增殖。我们首次报道了N-Myc下游调节基因2(NDRG2)是一个新的肿瘤抑制基因，与多种肿瘤有关，如胶质瘤、乳腺癌和结直肠癌。在此，我们提供了KLF4可以通过与NDRG2启动子结合而转录激活NDRG2的新证据。通过四甲基偶氮唑盐比色法、EDU染色、集落形成实验和小鼠移植瘤模型，我们证实了KLF4抑制了结直肠癌细胞的增殖和对NDRG2依赖的肿瘤的形成。最后，通过组织芯片分析发现，联合检测KLF4/NDRG2共表达与结直肠癌的TNM分级和分化程度呈正相关。KLF4和NDRG2在结直肠癌患者中的低表达与总体生存不良相关。因此，KLF4抑制依赖NDRG2信号的结直肠癌细胞的增殖，为结直肠癌的治疗和早期诊断提供了新的策略。
Kruppel-like factor 4 (KLF4) is a zinc finger transcription factor, which was confirmed as a tumor suppressor gene in colorectal cancers. KLF4 inhibits colorectal cancer cells proliferation through upregulating p21(WAF1/Cip1) and downregulating cyclin D1. We firstly reported that N-Myc downstream regulated gene 2 (NDRG2) was a novel tumor suppressor gene in multiple cancers, such as glioma, breast cancer and colorectal cancer. Herein, we provide novel evidence that KLF4 can transcriptionally activate NDRG2 by binding with NDRG2 promoter. With MTT assay, EdU staining, colony formation assay and xenograft mouse model, we confirmed that KLF4 inhibited colorectal cancer cell proliferation and tumorigenesis dependent on NDRG2. Finally, with tissue array analysis, we found a positive correlation of combined detection of KLF4/NDRG2 co-expression with TNM grades and differentiation levels of colorectal cancer. Lower expression of KLF4 and NDRG2 in colorectal cancer patients was correlated with poor overall survival. Thus, KLF4 inhibited the proliferation of colorectal cancer cells dependent on NDRG2 signaling, which provides a novel strategy for therapy and early diagnosis of colorectal cancer.