Rogler Anja, Kendziorra Emil, Giedl Johannes, Stoehr Christine, Taubert Helge, Goebell Peter J, Wullich Bernd, Stöckle Michael, Lehmann Jan, Petsch Sabrina, Hartmann Arndt, Stoehr Robert
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany.
J Cancer Res Clin Oncol. 2015 Oct;141(10):1779-90. doi: 10.1007/s00432-015-1942-1. Epub 2015 Mar 4.
We previously showed that the Wnt-signaling antagonist SFRP1 (secreted frizzled-related protein 1) is a promising marker in bladder cancer. The aim of this study was to validate the prognostic role and analyze the functional significance of SFRP1.
Four bladder cancer cell lines (RT112, RT4, J82 and BFTC905) and one urothelial cell line (UROtsa) were used for functional characterization of SFRP1 expression. Effects on viability, proliferation and wound healing were investigated, and canonical Wnt-pathway activity as well as Wnt-signaling target gene expression was analyzed. Additionally, tissue micro-arrays from two different bladder tumor cohorts were evaluated for SFRP1 expression, and associations with survival and histopathological parameters were analyzed.
The cell lines RT112, RT4, J82 and UROtsa showed SFRP1 expression. In BFTC905, SFRP1 expression was inhibited by promoter hypermethylation. Wnt-pathway activity was absent in all cell lines and independent from SFRP1 expression. RT112 and BFTC905 were used for further functional characterization. SFRP1 overexpression resulted in decreased viability and migration in BFTC905 cells. Knockdown of SFRP1 expression in RT112 cells resulted only in marginal effects. In bladder tumors, SFRP1 expression was associated with lower tumor grade, but not with progression in patients with papillary bladder cancer. SFRP1 expressing papillary bladder cancer tumors also demonstrated a tendency to longer overall survival.
SFRP1 is reducing malignant potential of BFTC905 cells, but not by regulation of canonical Wnt-signaling pathway. Other pathways, like non-canonical Wnt or the MAPK pathway, could be activated via SFRP1-expression loss. In bladder tumors, SFRP1 has the potential to predict outcome for a subset of papillary bladder tumors.
我们之前表明，Wnt信号拮抗剂SFRP1（分泌型卷曲相关蛋白1）是膀胱癌中有前景的标志物。本研究的目的是验证SFRP1的预后作用并分析其功能意义。
使用四种膀胱癌细胞系（RT112、RT4、J82和BFTC905）和一种尿路上皮细胞系（UROtsa）对SFRP1表达进行功能表征。研究其对活力、增殖和伤口愈合的影响，并分析经典Wnt通路活性以及Wnt信号靶基因表达。此外，对来自两个不同膀胱肿瘤队列的组织微阵列进行SFRP1表达评估，并分析其与生存和组织病理学参数的关联。
RT112细胞系、RT4细胞系、J82细胞系和UROtsa细胞系显示有SFRP1表达。在BFTC905细胞系中，SFRP1表达受到启动子高甲基化的抑制。所有细胞系中均不存在Wnt通路活性，且与SFRP1表达无关。使用RT112细胞系和BFTC905细胞系进行进一步的功能表征。SFRP1过表达导致BFTC905细胞活力和迁移能力下降。在RT112细胞系中敲低SFRP1表达仅产生轻微影响。在膀胱肿瘤中，SFRP1表达与较低的肿瘤分级相关，但与乳头状膀胱癌患者的病情进展无关。表达SFRP1的乳头状膀胱癌肿瘤也显示出总生存期较长的趋势。
SFRP1可降低BFTC905细胞的恶性潜能，但并非通过调节经典Wnt信号通路。其他通路，如非经典Wnt或MAPK通路，可能通过SFRP1表达缺失而被激活。在膀胱肿瘤中，SFRP1有可能预测一部分乳头状膀胱肿瘤的预后。
