FOXQ1 Is Overexpressed in Colorectal Cancer and Enhances Tumorigenicity and Tumor Growth
FOXQ1 Is Overexpressed in Colorectal Cancer and Enhances Tumorigenicity and Tumor Growth
复制标题
DOI：
10.1158/0008-5472.can-09-2161
复制
发表时间：
2010-03-01
期刊：
影响因子：
11.2
通讯作者：
Nishio, Kazuto
中科院分区：
文献类型：
--
作者：
Kaneda, Hiroyasu;Arao, Tokuzo;Nishio, Kazuto
叉头盒Q1（FOXQ 1）是叉头转录因子家族的成员，最近被提出参与小鼠胃酸分泌和粘蛋白基因表达。然而，FOXQ 1在人类特别是癌细胞中的作用仍然未知。我们发现FOXQ 1 mRNA在结直肠癌的临床标本中过表达（CRC; 28倍/结肠粘膜）。微阵列分析显示，使用小干扰RNA敲除FOXQ 1导致p21（CIP 1/WAF 1）表达下降，报告基因测定和染色质免疫沉淀测定显示p21是FOXQ 1的靶基因之一。稳定的FOXQ 1过表达细胞（H1299/FOXQ 1）表现出p21表达水平升高，并抑制阿霉素或喜树碱诱导的细胞凋亡。尽管H1299/FOXQ 1细胞在体外的细胞增殖减少，但H1299/FOXQ 1细胞在体内的致瘤性显著增加[增强型绿色荧光蛋白（EGFP）：2/15，FOXQ 1：7/15]，并增强肿瘤生长（437 +/- 301 vs. 1735 +/- 769 mm（3），P < 0.001）。同时，H1299/FOXQ 1细胞的稳定p21敲除增加了肿瘤生长，表明FOXQ 1促进肿瘤生长不依赖于p21。H1299/EGFP和H1299/FOXQ 1的微阵列分析显示，FOXQ 1过表达上调了几个对肿瘤生长具有积极作用的基因，包括VEGFA、WNT 3A、RSPO 2和BCL 11 A。肿瘤标本的CD 31和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记染色显示FOXQ 1过表达介导了体内血管生成和抗凋亡作用。总之，FOXQ 1在CRC中过表达，并可能通过其血管生成和抗凋亡作用增强致瘤性和肿瘤生长。我们的研究结果表明FOXQ 1是癌症相关FOX家族的新成员。Cancer Res; 70（5）; 2053-63. (C)2010年AACR。
Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family, and it has recently been proposed to participate in gastric acid secretion and mucin gene expression in mice. However, the role of FOXQ1 in humans and especially in cancer cells remains unknown. We found that FOXQ1 mRNA is overexpressed in clinical specimens of colorectal cancer (CRC; 28-fold/colonic mucosa). A microarray analysis revealed that the knockdown of FOXQ1 using small interfering RNA resulted in a decrease in p21(CIP1/WAF1) expression, and a reporter assay and a chromatin immunoprecipitation assay showed that p21 was one of the target genes of FOXQ1. Stable FOXQ1-overexpressing cells (H1299/FOXQ1) exhibited elevated levels of p21 expression and inhibition of apoptosis induced by doxorubicin or camptothecin. Although cellular proliferation was decreased in H1299/FOXQ1 cells in vitro, H1299/FOXQ1 cells significantly increased tumorigenicity [ enhanced green fluorescent protein (EGFP): 2/15, FOXQ1: 7/15] and enhanced tumor growth (437 +/- 301 versus 1735 +/- 769 mm(3), P < 0.001) in vivo. Meanwhile, stable p21 knockdown of H1299/FOXQ1 cells increased tumor growth, suggesting that FOXQ1 promotes tumor growth independent of p21. Microarray analysis of H1299/EGFP and H1299/FOXQ1 revealed that FOXQ1 overexpression upregulated several genes that have positive roles for tumor growth, including VEGFA, WNT3A, RSPO2, and BCL11A. CD31 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining of the tumor specimens showed that FOXQ1 overexpression mediated the angiogenic and antiapoptotic effect in vivo. In conclusion, FOXQ1 is overexpressed in CRC and enhances tumorigenicity and tumor growth presumably through its angiogenic and antiapoptotic effects. Our findings show that FOXQ1 is a new member of the cancer-related FOX family. Cancer Res; 70(5); 2053-63. (C) 2010 AACR.