Abstract
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.
Highlights
Breast cancer (BC) occurs commonly in women and is amongst the deadliest cancers (Center for Disease Control and Prevention (CDC), 2017; Wang et al, 2014b) as aggressive forms of BC are characterized by cells with high proliferation, migration, and invasion potential (Lambert et al, 2017) leading to cancer metastasis, the most common cause of cancer deaths
Breast cancer cell migration was suggested to be inhibited by Aspirin (Maity et al, 2015), and to confirm that hypothesis and to explore the possible involvement of the Wnt/β-catenin pathway, we performed transwell migration and invasion assays with highly metastatic MDA-MB-231 human mammary tumor cells and 4T1 mouse mammary tumor cells
These results indicate that the Wnt/β-catenin signaling pathway plays a role in promoting the metastasis of breast cancer, and Aspirin has strong antimetastatic effects and inhibits breast cancer cell migration and invasion (BCCMI) by acting on the Wnt/β-catenin signaling pathway, likely at some point downstream of LiCl activation
Summary
Breast cancer (BC) occurs commonly in women and is amongst the deadliest cancers (Center for Disease Control and Prevention (CDC), 2017; Wang et al, 2014b) as aggressive forms of BC are characterized by cells with high proliferation, migration, and invasion potential (Lambert et al, 2017) leading to cancer metastasis, the most common cause of cancer deaths. Wnt/β-Catenin, Fibromodulin, Cancer Metastasis, and Aspirin extracellular matrix (ECM) is known to regulate diverse cellular functions, including proliferation, migration, differentiation, and play crucial roles in normal physiology and many pathological processes including cancer (Kim et al, 2011; Bonnans et al, 2014). The ECM is recognized as an important regulator and tumor microenvironment in breast cancer, and many ECM components including proteoglycans play key roles in BC progression and metastasis (Insua-Rodriguez and Oskarsson, 2016). Fibromodulin (FMOD) is a small leucine-rich proteoglycan ECM protein, and is a member of a family of secreted proteoglycans that play important roles in signaling, collagen fibrillogenesis, cell migration, adhesion, growth, differentiation, and apoptosis (Pietraszek-Gremplewicz et al, 2019), while individual members have different functions and effects on cancer (Iozzo and Sanderson, 2011; Edwards, 2012). FMOD was suggested to be a tumor-associated antigen in chronic lymphocytic leukemia (CLL) (Mayr et al, 2005); in clinical samples obtained from prostate cancer patients, significant variations of FMOD expression were observed between benign and malignant tissues (Reyes et al, 2016); and a recent study implicated FMOD in glioma cell migration (Mondal et al, 2017)
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