Colon cancer progression is driven by APEX1-mediated upregulation of Jagged
Colon cancer progression is driven by APEX1-mediated upregulation of Jagged
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DOI：
10.1172/jci65521
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发表时间：
2013-08-01
影响因子：
15.9
通讯作者：
You, Ho Jin
中科院分区：
文献类型：
--
作者：
Kim, Mi-Hwa;Kim, Hong-Beum;You, Ho Jin
在许多人类实体瘤中已经报道了脱嘌呤-脱嘧啶核酸内切酶-1（APEX 1）的异常表达，并且与癌症进展呈正相关;然而，APEX 1在肿瘤进展中的作用定义不清。在这里，我们发现APEX 1有助于侵袭性结肠癌行为，并在Jagged 1/Notch信号通路中作为上游激活剂发挥作用。人结肠癌细胞系中APEX 1过表达或敲低诱导恶性性质的深刻变化，如细胞增殖、锚定非依赖性生长、迁移、侵袭和体外血管生成以及小鼠异种移植模型中的肿瘤形成和转移。APEX 1的这些致癌作用是通过上调主要Notch配体Jagged 1介导的。此外，APEX 1表达与Jagged 1在各种结肠癌细胞系和结肠癌患者的组织中相关。这一发现将APEX 1鉴定为Jagged 1/Notch活性的正调节因子，并表明它是表现出高水平Jagged 1/Notch信号传导的结肠癌的潜在治疗靶点。
Aberrant expression of apurinic-apyrimidinic endonuclease-1 (APEX1) has been reported in numerous human solid tumors and is positively correlated with cancer progression; however, the role of APEX1 in tumor progression is poorly defined. Here, we show that APEX1 contributes to aggressive colon cancer behavior and functions as an upstream activator in the Jagged1/Notch signaling pathway. APEX1 overexpression or knockdown in human colon cancer cell lines induced profound changes in malignant properties such as cell proliferation, anchorage-independent growth, migration, invasion, and angiogenesis in vitro and in tumor formation and metastasis in mouse xenograft models. These oncogenic effects of APEX1 were mediated by the upregulation of Jagged1, a major Notch ligand. Furthermore, APEX1 expression was associated with Jagged1 in various colon cancer cell lines and in tissues from colon cancer patients. This finding identifies APEX1 as a positive regulator of Jagged1/Notch activity and suggests that it is a potential therapeutic target in colon cancers that exhibit high levels of Jagged1/Notch signaling.