Le Rolle Anne-France, Chiu Thang K, Zeng Zhaoshi, Shia Jinru, Weiser Martin R, Paty Philip B, Chiu Vi K
Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA.
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Oncotarget. 2016 Jan 19;7(3):2159-74. doi: 10.18632/oncotarget.6818.
Colorectal cancer is the third most frequently diagnosed cancer worldwide. Prevention of colorectal cancer initiation represents the most effective overall strategy to reduce its associated morbidity and mortality. Activating KRAS mutation (KRASmut) is the most prevalent oncogenic driver in colorectal cancer development, and KRASmut inhibition represents an unmet clinical need. We apply a systems-level approach to study the impact of KRASmut on stem cell signaling during human colon cancer initiation by performing gene set enrichment analysis on gene expression from human colon tissues. We find that KRASmut imposes the embryonic stem cell-like program during human colon cancer initiation from colon adenoma to stage I carcinoma. Expression of miR145, an embryonic SC program inhibitor, promotes cell lineage differentiation marker expression in KRASmut colon cancer cells and significantly suppresses their tumorigenicity. Our data support an in vivo plasticity model of human colon cancer initiation that merges the intrinsic stem cell properties of aberrant colon stem cells with the embryonic stem cell-like program induced by KRASmut to optimize malignant transformation. Inhibition of the embryonic SC-like program in KRASmut colon cancer cells reveals a novel therapeutic strategy to programmatically inhibit KRASmut tumors and prevent colon cancer.
结直肠癌是全球第三大最常被诊断出的癌症。预防结直肠癌的发生是降低其相关发病率和死亡率的最有效总体策略。激活型KRAS突变（KRASmut）是结直肠癌发展过程中最常见的致癌驱动因素，而抑制KRASmut代表了一种尚未满足的临床需求。我们应用系统水平的方法，通过对人类结肠组织的基因表达进行基因集富集分析，来研究KRASmut在人类结肠癌起始过程中对干细胞信号传导的影响。我们发现，在从结肠腺瘤到I期癌的人类结肠癌起始过程中，KRASmut会施加类似胚胎干细胞的程序。miR145是一种胚胎干细胞程序抑制剂，其表达可促进KRASmut结肠癌细胞中细胞谱系分化标志物的表达，并显著抑制其致瘤性。我们的数据支持一种人类结肠癌起始的体内可塑性模型，该模型将异常结肠干细胞的内在干细胞特性与KRASmut诱导的类似胚胎干细胞的程序相结合，以优化恶性转化。抑制KRASmut结肠癌细胞中类似胚胎干细胞的程序揭示了一种以编程方式抑制KRASmut肿瘤并预防结肠癌的新治疗策略。
