DataSheet_1_Wnt/β-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin.pdf

Emerging evidence suggests that fibromodulin (FMOD), an extracellular matrix protein, is associated with cancer, and yet little is known about the regulation of FMOD expression and its role in cancer metastasis. Aspirin, a classic anti-inflammatory drug, has been indicated to offer anticancer benefits, but its action targets and mechanisms remain obscure. In the present study using cell lines, animal model and database analysis, we show that FMOD is crucial for breast cancer cell migration and invasion (BCCMI) via activation of ERK; expression of FMOD is regulated positively by the Wnt/β-catenin pathway, wherein the β-catenin/TCF4/LEF1 complex binds the FMOD promoter to transcribe FMOD. Aspirin inhibits BCCMI by attenuating Wnt/β-catenin signaling and suppressing FMOD expression via inhibiting deacetylation of β-catenin by histone deacetylase 6 (HDAC6) leading to β-catenin phosphorylation and cytoplasmic degradation. Moreover, expression of the transcriptional complex components β-catenin/TCF4/LEF1 is upregulated by the Wnt/β-catenin pathway, constituting positive feedback loops that amplify its signal output. Our findings identify a critical role of FMOD in cancer metastasis, reveal a mechanism regulating FMOD transcription and impacting tumor metastasis, uncover action targets and mechanism for the anticancer activity of Aspirin, and expand the understanding of the Wnt/β-catenin pathway and tumor metastasis, which are valuable for development of cancer therapeutics.

越来越多的研究证据表明，细胞外基质蛋白纤维调节蛋白（fibromodulin, FMOD）与癌症存在关联，但目前对于FMOD的表达调控机制及其在肿瘤转移中的作用仍知之甚少。经典抗炎药物阿司匹林虽被报道具有抗癌益处，但其作用靶点与具体分子机制仍不明确。本研究通过细胞系、动物模型及数据库分析展开，结果显示FMOD可通过激活ERK促进乳腺癌细胞迁移与侵袭（BCCMI）；FMOD的表达受Wnt/β-连环蛋白信号通路（Wnt/β-catenin pathway）正向调控，该通路中β-连环蛋白/TCF4/LEF1复合物可结合FMOD启动子以启动FMOD的转录。阿司匹林可通过减弱Wnt/β-连环蛋白信号通路、抑制FMOD表达来阻断BCCMI：其具体机制为通过抑制组蛋白去乙酰化酶6（HDAC6）对β-连环蛋白的去乙酰化修饰，进而引发β-连环蛋白磷酸化并发生胞质降解。此外，Wnt/β-连环蛋白信号通路可上调转录复合物组分β-连环蛋白/TCF4/LEF1的表达，形成正反馈环路以放大通路的信号输出。本研究结果明确了FMOD在肿瘤转移中的关键作用，揭示了调控FMOD转录并影响肿瘤转移的分子机制，阐明了阿司匹林发挥抗癌活性的作用靶点与具体机制，同时加深了学界对Wnt/β-连环蛋白信号通路及肿瘤转移的认知，相关发现对于癌症治疗药物的研发具有重要价值。