PHF21B overexpression promotes cancer stem cell-like traits in prostate cancer cells by activating the Wnt/β-catenin signaling pathway.
PHF21B overexpression promotes cancer stem cell-like traits in prostate cancer cells by activating the Wnt/β-catenin signaling pathway.
复制标题
PHF21B 过表达通过激活 Wnt/β-catenin 信号通路促进前列腺癌细胞中的癌症干细胞样特征
DOI：
10.1186/s13046-017-0560-y
复制
发表时间：
2017-06-23
期刊：
影响因子：
--
通讯作者：
Peng X
中科院分区：
文献类型：
--
作者：
Li Q;Ye L;Guo W;Wang M;Huang S;Peng X
背景PHF 21 B是新近发现的参与前列腺癌发生发展的因子，但其在前列腺癌中的生物学作用和分子机制尚不清楚。本研究旨在探讨PHF 21 B在前列腺癌发生、发展中的作用。方法采用Real-time PCR、免疫组化和Western blotting方法检测PHF 21 B在前列腺癌细胞系和临床标本中的表达。PHF 21 B在维持前列腺癌干细胞样表型中的作用通过肿瘤球形成测定和干细胞标志物的表达水平来检查。采用荧光素酶报告基因分析、蛋白质印迹分析、酶联免疫吸附试验和ChIP试验检测PHF 21 B是否通过下调SFRP 1和SFRP 2激活Wnt/β-catenin信号通路。高PHF 21 B水平预测前列腺癌患者的无复发生存率较差。功能获得和功能丧失研究表明，PHF 21 B的过表达增强了前列腺癌细胞中的癌症干细胞样表型，而下调则抑制了前列腺癌细胞中的癌症干细胞样表型。异种移植瘤模型显示沉默PHF 21 B降低了体内致瘤能力。值得注意的是，Wnt/β-连环蛋白信号在过表达PHF 21 B的前列腺癌细胞中被过度激活，并介导PHF 21 B诱导的癌症干细胞样表型。此外，PHF 21 B抑制Wnt/β-catenin信号级联的阻遏物，包括SFRP 1和SFRP 2。这些结果表明，PHF 21 B通过转录下调SFRP 1和SFRP 2组成性激活wnt/β-catenin信号通路，促进前列腺癌干细胞样表型的形成。
BackgroundPHF21B is newly identified to be involved in the tumor progression; however, its biological role and molecular mechanism in prostate cancer have not been defined. This study is aimed to study the role of PHF21B in the progression of prostate cancer.MethodsReal-time PCR, immunohistochemistry and western blotting analysis were used to determine PHF21B expression in prostate cancer cell lines and clinical specimens. The role of PHF21B in maintaining prostate cancer stem cell-like phenotype was examined by tumor-sphere formation assay and expression levels of stem cell markers. Luciferase reporter assay, western blot analysis, enzyme-linked immunosorbent assay and ChIP assay were used to determine whether PHF21B activates the Wnt/β-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2.ResultsOur results revealed that PHF21B was markedly upregulated in prostate cancer cell lines and tissues. High PHF21B levels predicted poorer recurrence-free survival in prostate cancer patients. Gain-of-function and loss-of-function studies showed that overexpression of PHF21B enhanced, while downregulation suppressed, the cancer stem cell-like phenotype in prostate cancer cells. Xenograft tumor model showed that silencing PHF21B decreased the ability of tumorigenicity in vivo. Notably, Wnt/β-catenin signaling was hyperactivated in prostate cancer cells overexpressing PHF21B, and mediated PHF21B-induced cancer stem cell-like phenotype. Furthermore, PHF21B suppressed repressors of the Wnt/β-catenin signaling cascade, including SFRP1 and SFRP2. These results demonstrated that PHF21B constitutively activated wnt/β-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2, which promotes prostate cancer stem cell-like phenotype.ConclusionsOur results revealed that PHF21B functions as an oncogene in prostate cancer, and may represent a promising prognostic biomarker and an attractive candidate for target therapy of prostate cancer.