Adrenomedullin is a therapeutic target in colorectal cancer.
Adrenomedullin is a therapeutic target in colorectal cancer.
复制标题
肾上腺髓质素是结直肠癌的治疗靶点。
DOI：
10.1002/ijc.28542
复制
发表时间：
2014-05-01
影响因子：
6.4
通讯作者：
Chung, Daniel C.
中科院分区：
文献类型：
--
作者：
Wang, Liangjing;Gala, Manish;Yamamoto, Masayoshi;Pino, Maria S.;Kikuchi, Hirotoshi;Shue, Daniel S.;Shirasawa, Senji;Austin, Thomas R.;Lynch, Maureen P.;Rueda, Bo R.;Zukerberg, Lawrence R.;Chung, Daniel C.
KRAS癌基因影响结直肠癌（CRC）的血管生成、转移和化疗耐药性，这些过程在缺氧条件下都会增强。为了确定突变型KRAS在缺氧微环境中的功能活性，我们首先在仅通过突变型KRAS（K-ras D13）的表达而不同的同基因DKs 5和DKO 3结肠癌细胞系中进行cDNA微阵列实验。肾上腺髓质素（ADM）被确定为在低氧条件下表达KRAS癌基因的DKs 5细胞中最显著上调的基因之一（3.2倍，p=1.47×10−5）。突变型KRAS（K-ras V12）在Caco-2细胞（K-ras WT）中的异位表达可诱导ADM的表达，而选择性敲低突变型KRAS等位基因（K-ras D13或K-ras V12）在HCT 116、DLD 1和SW 480结肠癌细胞中可抑制低氧下ADM的表达。在结肠肿瘤异种移植物中，ADM的敲低阻断血管生成并刺激凋亡，导致肿瘤抑制。此外，ADM还能调节结肠癌细胞的体外侵袭。在56例CRC患者中，在携带KRAS突变的样本中观察到ADM的表达水平显著较高。总之，ADM是缺氧环境下致癌KRAS的新靶点。这一观察结果表明，治疗靶点可能因特定的肿瘤微环境而异。
The KRAS oncogene influences angiogenesis, metastasis, and chemoresistance in colorectal cancers (CRC), and these processes are all enhanced in hypoxic conditions. In order to define functional activities of mutant KRAS in a hypoxic microenvironment, we first performed cDNA microarray experiments in isogenic DKs5 and DKO3 colon cancer cell lines that differ only by their expression of mutant KRAS (K-ras D13). Adrenomedullin (ADM) was identified as one of the most significantly upregulated genes in DKs5 cells that express the KRAS oncogene in hypoxia (3.2-fold, p=1.47×10−5). Ectopic expression of mutant KRAS (K-ras V12) in Caco-2 cells (K-ras WT) induced ADM, while selective knockdown of mutant KRAS alleles (K-ras D13 or K-ras V12) in HCT116, DLD1, and SW480 colon cancer cells suppressed the expression of ADM in hypoxia. Knockdown of ADM in colon tumor xenografts blocked angiogenesis and stimulated apoptosis, resulting in tumor suppression. Furthermore, ADM also regulated colon cancer cell invasion in vitro. Among 56 patients with CRC, significantly higher expression levels of ADM were observed in samples harboring a KRAS mutation. Collectively, ADM is a new target of oncogenic KRAS in the setting of hypoxia. This observation suggests that therapeutic targets may differ depending upon the specific tumor microenvironment.
登录
查看更多内容
影响因子：
6.4
作者：
Keleg, Shereen;Kayed, Hany;Kleeff, Joerg
通讯作者：
Kleeff, Joerg
影响因子：
14.9
作者：
Benita Y;Kikuchi H;Smith AD;Zhang MQ;Chung DC;Xavier RJ
通讯作者：
Xavier RJ
影响因子：
8
作者：
Oehler, MK;Norbury, C;Bicknell, R
通讯作者：
Bicknell, R
影响因子：
4.8
作者：
Mizukami, Yusuke;Fujiki, Kotoyo;Chung, Daniel C.
通讯作者：
Chung, Daniel C.
影响因子：
11.2
作者：
Ramachandran, Vijaya;Arumugam, Thiruvengadam;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.