The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
Department of Pathogenic Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
Oncol Rep. 2017 Aug;38(2):975-984. doi: 10.3892/or.2017.5736. Epub 2017 Jun 21.
Krüppel-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 p21WAF1/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.
Krüppel 样因子 4（KLF4）是一种锌指转录因子，在结直肠癌中被确认为肿瘤抑制基因。KLF4 通过上调 p21WAF1/Cip1 和下调细胞周期蛋白 D1 来抑制结肠直肠癌细胞增殖。我们首次报道，N- Myc 下游调节基因 2（NDRG2）是一种在多种癌症（如神经胶质瘤、乳腺癌和结直肠癌）中具有新型肿瘤抑制基因的基因。在此，我们提供了新的证据，证明 KLF4 可以通过与 NDRG2 启动子结合来转录激活 NDRG2。通过 MTT 检测、EdU 染色、集落形成检测和异种移植小鼠模型，我们证实 KLF4 依赖于 NDRG2 抑制结肠直肠癌细胞的增殖和肿瘤发生。最后，通过组织芯片分析，我们发现 KLF4/NDRG2 共表达的联合检测与结直肠癌的 TNM 分级和分化水平呈正相关。结直肠癌患者中 KLF4 和 NDRG2 的低表达与总生存期较差相关。因此，KLF4 依赖于 NDRG2 信号抑制结肠直肠癌细胞的增殖，为结直肠癌的治疗和早期诊断提供了新的策略。
