Rose Michael, Schubert Claudia, Dierichs Laura, Gaisa Nadine T, Heer Matthias, Heidenreich Axel, Knüchel Ruth, Dahl Edgar
a Molecular Oncology Group; Institute of Pathology ; RWTH Aachen University ; Aachen , Germany.
Epigenetics. 2014 Dec;9(12):1626-40. doi: 10.4161/15592294.2014.988052.
CREB3L1 has been recently proposed as a novel metastasis suppressor gene in breast cancer. Our current study highlights CREB3L1 expression, regulation, and function in bladder cancer. We demonstrate a significant downregulation of CREB3L1 mRNA expression (n = 64) in primary bladder cancer tissues caused by tumor-specific CREB3L1 promoter hypermethylation (n = 51). Based on pyrosequencing CREB3L1 methylation was shown to be potentially associated with a more aggressive phenotype of bladder cancer. These findings were verified by an independent public data set containing data from 184 bladder tumors. In addition, immunohistochemical evaluation showed that CREB3L1 protein expression is decreased in bladder cancer tissues as well. Interestingly, protein loss is predominately observed in the nuclei of aggressive tumor cells. Based on in vitro models we clearly show that CREB3L1 re-expression mediates suppression of tumor cell migration and colony growth of high grade and invasive bladder cancer cells. The candidate tumor suppressor and TGF-β signaling inhibitor HTRA3 was furthermore identified as putative target gene of CREB3L1 in both invasive J82 bladder cells and primary bladder tumors. Hence, our data provide for the first time evidence that the transcription factor CREB3L1 may have an important role as a putative tumor suppressor in bladder cancer.
CREB3L1最近被认为是乳腺癌中的一种新型转移抑制基因。我们目前的研究着重于CREB3L1在膀胱癌中的表达、调控及功能。我们证实在原发性膀胱癌组织中（n = 64），肿瘤特异性CREB3L1启动子高甲基化（n = 51）导致CREB3L1 mRNA表达显著下调。基于焦磷酸测序，CREB3L1甲基化显示可能与膀胱癌更具侵袭性的表型相关。这些发现通过一个包含184个膀胱肿瘤数据的独立公共数据集得到验证。此外，免疫组化评估显示CREB3L1蛋白表达在膀胱癌组织中也降低。有趣的是，蛋白缺失主要在侵袭性肿瘤细胞核中观察到。基于体外模型，我们清楚地表明CREB3L1的重新表达介导了对高级别和侵袭性膀胱癌细胞的肿瘤细胞迁移及集落生长的抑制。候选肿瘤抑制因子及TGF-β信号抑制剂HTRA3在侵袭性J82膀胱癌细胞和原发性膀胱肿瘤中均被鉴定为CREB3L1的假定靶基因。因此，我们的数据首次提供了证据表明转录因子CREB3L1可能作为一种假定的肿瘤抑制因子在膀胱癌中发挥重要作用。
