Blanchard Thomas G, Czinn Steven J, Banerjee Vivekjyoti, Sharda Neha, Bafford Andrea C, Mubariz Fahad, Morozov Dennis, Passaniti Antonino, Ahmed Hafiz, Banerjee Aditi
Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Cancers (Basel). 2019 Feb 8;11(2):199. doi: 10.3390/cancers11020199.
Metastatic colorectal cancer (mCRC) is characterized by the expression of cellular oncogenes, the loss of tumor suppressor gene function. Therefore, identifying integrated signaling between onco-suppressor genes may facilitate the development of effective therapy for mCRC. To investigate these pathways we utilized cell lines and patient derived organoid models for analysis of gene/protein expression, gene silencing, overexpression, and immunohistochemical analyses. An inverse relationship in expression of oncogenic FoxM1 and tumor suppressor RASSF1A was observed in various stages of CRC. This inverse correlation was also observed in mCRC cells lines (T84, Colo 205) treated with Akt inhibitor. Inhibition of FoxM1 expression in mCRC cells as well as in our ex vivo model resulted in increased RASSF1A expression. Reduced levels of RASSF1A expression were found in normal cells (RWPE-1, HBEpc, MCF10A, EC) stimulated with exogenous VEGF. Downregulation of FoxM1 also coincided with increased YAP phosphorylation, indicative of tumor suppression. Conversely, downregulation of RASSF1A coincided with FoxM1 overexpression. These studies have identified for the first time an integrated signaling pathway between FoxM1 and RASSF1A in mCRC progression, which may facilitate the development of novel therapeutic options for advanced colon cancer therapy.
转移性结直肠癌（mCRC）的特征在于细胞癌基因的表达以及肿瘤抑制基因功能的丧失。因此，确定癌基因与抑癌基因之间的整合信号传导可能有助于开发针对mCRC的有效治疗方法。为了研究这些途径，我们利用细胞系和患者来源的类器官模型进行基因/蛋白质表达分析、基因沉默、过表达和免疫组织化学分析。在结直肠癌的各个阶段均观察到致癌性FoxM1和肿瘤抑制因子RASSF1A表达呈负相关。在用Akt抑制剂处理的mCRC细胞系（T84、Colo 205）中也观察到这种负相关。在mCRC细胞以及我们的体外模型中抑制FoxM1表达会导致RASSF1A表达增加。在用外源性VEGF刺激的正常细胞（RWPE-1、HBEpc、MCF10A、EC）中发现RASSF1A表达水平降低。FoxM1的下调还与YAP磷酸化增加同时出现，这表明具有肿瘤抑制作用。相反，RASSF1A的下调与FoxM1过表达同时出现。这些研究首次确定了FoxM1和RASSF1A在mCRC进展过程中的整合信号通路，这可能有助于开发用于晚期结肠癌治疗的新型治疗方案。
