M&M Medical BioInformatics, Hongo 113-0033, Japan.
Int J Oncol. 2010 Feb;36(2):415-20. doi: 10.3892/ijo_00000514.
CXCR4, CD133, CD44 and ABCG2 are representative transmembrane proteins expressed on the surfaces of normal and/or cancer stem cells. CXCR4 is co-expressed with POU5F1 in endodermal precursors and adult-tissue stem cells. CXCR4 is expressed in a variety of human tumors, such as breast cancer, prostate cancer, pancreatic cancer, and gastric cancer. CXCR4 is a G protein-coupled receptor (GPCR) for CXCL12 (SDF1) chemokine, and the CXCL12-CXCR4 signaling axis is involved in proliferation, survival, migration, and homing of cancer cells. Integrative genomic analyses of CXCR4 gene were carried out to elucidate the mechanisms of CXCR4 expression in stem cells, because CXCR4 is a key molecule occupying the crossroads of oncology, immunology, gerontology and regenerative medicine. Human CXCR4 promoter region with binding sites for HIF1alpha, ETS1, NF-kappaB and GLI was not conserved in mouse and rat Cxcr4 orthologs. Proximal enhancer region with palindromic Smad-binding sites, FOX-binding site, POU-binding site, triple SOX17-binding sites, bHLH-binding site, TCF/LEF-binding site, and double GFI1-binding sites was almost completely conserved among human, chimpanzee, mouse, and rat CXCR4 orthologs. TGFbeta, Nodal, and Activin signals induce CXCR4 upregulation based on Smad2/3 and FOX family members, such as FOXA2, FOXC2, and FOXH1. CXCR4 is expressed in endodermal precursors due to the existence of triple SOX17-binding sites around the POU-binding site instead of the POU5F1-SOX2 joint motif. Because CXCR4 is downregulated by p53-GFI1 signaling axis, p53 mutation in cancer stem cells leads to CXCR4 upregulation. CXCR4 is also upregulated by TGFbeta and Hedgehog signals in tumor cells at the invasion front. Small molecule compound or human antibody targeted to CXCR4 will be applied for cancer therapeutics focusing on cancer stem cells at the primary lesion as well as metastasis or recurrence niches, such as bone marrow and peritoneal cavity.
CXCR4、CD133、CD44 和 ABCG2 是正常和/或癌症干细胞表面表达的代表性跨膜蛋白。CXCR4 与内胚层前体细胞和成人组织干细胞中的 POU5F1 共同表达。CXCR4 在多种人类肿瘤中表达，如乳腺癌、前列腺癌、胰腺癌和胃癌。CXCR4 是 CXCL12（SDF1）趋化因子的 G 蛋白偶联受体（GPCR），CXCL12-CXCR4 信号轴参与癌细胞的增殖、存活、迁移和归巢。对 CXCR4 基因进行整合基因组分析，以阐明干细胞中 CXCR4 表达的机制，因为 CXCR4 是占据肿瘤学、免疫学、老年学和再生医学交叉点的关键分子。人类 CXCR4 启动子区域与 HIF1alpha、ETS1、NF-kappaB 和 GLI 的结合位点在鼠和大鼠 Cxcr4 同源物中没有保守。具有回文 Smad 结合位点、FOX 结合位点、POU 结合位点、三重 SOX17 结合位点、bHLH 结合位点、TCF/LEF 结合位点和双 GFI1 结合位点的近端增强子区域在人类、黑猩猩、小鼠和大鼠 CXCR4 同源物中几乎完全保守。TGFbeta、Nodal 和 Activin 信号通过 Smad2/3 和 FOX 家族成员（如 FOXA2、FOXC2 和 FOXH1）诱导 CXCR4 上调。由于 POU 结合位点周围存在三重 SOX17 结合位点，而不是 POU5F1-SOX2 联合基序，CXCR4 在内胚层前体细胞中表达。由于 CXCR4 被 p53-GFI1 信号轴下调，因此癌症干细胞中的 p53 突变导致 CXCR4 上调。TGFbeta 和 Hedgehog 信号也在肿瘤细胞侵袭前沿上调 CXCR4。针对 CXCR4 的小分子化合物或人抗体将应用于癌症治疗，重点关注原发性病变以及转移或复发部位（如骨髓和腹腔）中的癌症干细胞。
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