MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer.
MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer.
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DOI：
10.18632/oncotarget.2221
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发表时间：
2014-08-15
期刊：
影响因子：
--
通讯作者：
Catto JW
中科院分区：
文献类型：
--
作者：
Drayton RM;Peter S;Myers K;Miah S;Dudziec E;Bryant HE;Catto JW
膀胱尿路上皮细胞癌 (UCC) 是一种常见疾病，通常以 FGFR3 失调为特征。虽然这种癌基因的上调最常发生在低级别非侵袭性肿瘤中，但最近的数据显示，FGFR3 表达增加是侵袭性 UCC 的常见亚型的特征，与乳腺癌具有分子相似性。这些相似之处包括 FOXA1 转录因子的上调和 microRNAs-99a/100 表达的减少。我们之前已经确定了这两种 microRNA 对 FGFR3 的直接调节，现在正在寻找进一步的靶点。使用微阵列元数据库，我们发现 microRNAs-99a/100 可能对 FOXA1 进行调节。我们确认 microRNAs-99a/100 直接靶向 FOXA1 3'UTR，并且还通过 microRNA-485-5p/SOX5/JUN-D/FOXL1 和 microRNA-486/FOXO1a 进行潜在的间接调节。在 292 个良性和恶性尿路上皮样本中，我们发现 FOXA1 和 microRNAs-99a/100 的表达之间呈负相关（r=-0.33 至 -0.43，p<0.05）。对于UCC中的FGFR3，FOXA1高表达的肿瘤比低表达的肿瘤进展率更低（Logrank p=0.009）。使用全局基因表达和 CpG 甲基化分析，我们发现了 UCC 中 FOXA1 上调的基因型后果。遗传变化与区域低甲基化相关，发生在 FOXA1 结合位点附近，并且反映了先前在 FGFR3 突变体 UCC 中报道的基因表达变化。这些包括通过异常高甲基化（例如 IGFBP3）进行的基因沉默，以及影响表征乳腺癌亚型的基因（例如 ERBB2）。总之，我们发现 microRNA-99a/100 介导 FGFR3 和 FOXA1 之间的直接关系，并可能促进 UCC 中这些途径之间的串扰。
Urothelial cell carcinoma of the bladder (UCC) is a common disease often characterized by FGFR3 dysregulation. Whilst upregulation of this oncogene occurs most frequently in low-grade non-invasive tumors, recent data reveal increased FGFR3 expression characterizes a common sub-type of invasive UCC sharing molecular similarities with breast cancer. These similarities include upregulation of the FOXA1 transcription factor and reduced expression of microRNAs-99a/100. We have previously identified direct regulation of FGFR3 by these two microRNAs and now search for further targets. Using a microarray meta-database we find potential FOXA1 regulation by microRNAs-99a/100. We confirm direct targeting of the FOXA1 3′UTR by microRNAs-99a/100 and also potential indirect regulation through microRNA-485-5p/SOX5/JUN-D/FOXL1 and microRNA-486/FOXO1a. In 292 benign and malignant urothelial samples, we find an inverse correlation between the expression of FOXA1 and microRNAs-99a/100 (r=−0.33 to −0.43, p<0.05). As for FGFR3 in UCC, tumors with high FOXA1 expression have lower rates of progression than those with low expression (Log rank p=0.009). Using global gene expression and CpG methylation profiling we find genotypic consequences of FOXA1 upregulation in UCC. Genetic changes are associated with regional hypomethylation, occur near FOXA1 binding sites, and mirror gene expression changes previously reported in FGFR3 mutant-UCC. These include gene silencing through aberrant hypermethylation (e.g. IGFBP3) and affect genes characterizing breast cancer sub-types (e.g. ERBB2). In conclusion, we have identified microRNAs-99a/100 mediate a direct relationship between FGFR3 and FOXA1 and potentially facilitate cross talk between these pathways in UCC.
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