Dataset Information

Wnt/?-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin.

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/?-catenin pathway, wherein the ?-catenin/TCF4/LEF1 complex binds the FMOD promoter to transcribe FMOD. Aspirin inhibits BCCMI by attenuating Wnt/?-catenin signaling and suppressing FMOD expression via inhibiting deacetylation of ?-catenin by histone deacetylase 6 (HDAC6) leading to ?-catenin phosphorylation and cytoplasmic degradation. Moreover, expression of the transcriptional complex components ?-catenin/TCF4/LEF1 is upregulated by the Wnt/?-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/?-catenin pathway and tumor metastasis, which are valuable for development of cancer therapeutics.

SUBMITTER: Khan FU

PROVIDER: S-EPMC6886402 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Khan Fahim Ullah FU Owusu-Tieku Nana Yaa Gyaama NYG Dai Xiaoyong X Liu Kewei K Wu Yanping Y Tsai Hsiang-I HI Chen Hongbo H Sun Chunhui C Huang Laiqiang L

Frontiers in pharmacology 20191125

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 i ...[more]

PMID: 31824307

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Project description:Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronectin-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.

Dataset Information

Wnt/?-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin.

Publications

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

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