Fibulin-3 sponges Tiam1 to manipulate MMP-7 activity through β-catenin signaling in oral squamous cell carcinoma

Abstract

Purpose: Oral squamous cell carcinoma (named OSCC) is considered as the most frequent malignancy in oral cavity, which has became a rapid increasing problem for the global public health with unclear underling molecular mechanism. Previously, we reported Tiam1 (T-lymphoma invasion and metastasis inducing factor 1) as a potential oncogene for OSCC. Here, we in-depth explored its signaling mechanism.Methods: The mRNA and protein expression levels of primary differentially expressed genes (Tiam1, Fibulin-3 and MMP-7) were measured in different TNM stages of OSCC patients using RT-PCR and ELISA respectively. Using human OSCC cell line CAL27 cell line, the relationships between these factors have been analyzed and the direct interaction has been also examined. The luciferase reporter assay was established for the promoter region of MMP-7. Both the epithelial (E-cadherin) and mesenchymal protein markers (Vimentin and Snail) have been investigated using western blotting.Results: The mRNA and protein activities of Fibulin-3 declined as the increase of TNM stage. Inversely, the mRNA and protein levels of Tiam1 and MMP-7 elevated signi cantly as OSCC progressed. Tiam1 transfection in CAL27 cells stimulated the expression of MMP-7 by accelerating the nuclear translocation of β-catenin, which was opposite to the functions of Fibulin-3. Moreover, Tiam1 interacted directly with Fibulin-3. The Tiam1 induced OSCC epithelial-mesenchymal transition (EMT) via MMP-7 activation, which was dependent of β-catenin direct binding on the promoter region.Conclusions: Collectively, these results indicated that Tiam1 competed with Fibulin-3 for nuclear βcatenin translocation, which subsequently stimulated MMP-7 expression by TCF-4 domain interaction following EMT initiation in OSCC development. Our systematical work here hypothesized an innovative signaling cassette for OSCC progression, which provided bene cial references for future clinical study.

Matricellular proteins: Potential biomarkers in head and neck cancer

“…Tiam1 has been reported as a potential oncogene in oral squamous cell carcinoma. In this study, Tiam1 directly interacts with Fibulin‐3 to compete for the nuclear translocation of β‐catenin, and then stimulates the expression of MMP‐7 through the interaction of TCF‐4 domain to promote EMT 139 . In addition, Chen et al 140 .…”

“…In this study, Tiam1 directly interacts with Fibulin-3 to compete for the nuclear translocation of β-catenin, and then stimulates the expression of MMP-7 through the interaction of TCF-4 domain to promote EMT. 139 In addition, Chen et al 140 found that the expression of Fibulin-4 is increased in esophageal squamous cell carcinoma, and its down-regulation inhibits the proliferation, invasion and migration of cancer cells in vitro and in vivo. Inhibition of Fibulin-4 expression inhibits cell protective autophagy by activating Akt-mTOR signaling pathway, thus enhancing cell sensitivity to apatinib.…”

Impact of Rehydration Following Systemic Dehydration on Vocal Fold Gene Expression

“…The differential regulation of genes identified herein expands our understanding of hydration homeostasis as it pertains to vocal fold tissue and lays preliminary groundwork to explore the molecular basis of dehydration‐related voice changes more comprehensively. EFEMP1 , upregulated by dehydration in vocal folds, encodes Fibulin‐3 that regulates elastin stability, a major structural component of the vocal folds, and fibroblast activity in various conditions such as direct inguinal hernia, 23 cancer‐associated phenotypes, 24,25 and vascular endothelial function 26 . CLIC5 , also upregulated in the Dehydration group, is an intracellular ion channel with important pleiotropic effects on epithelial cell maintenance through interaction with the cytoskeleton 27,28 ; it was reported to contribute to the response to cardiac ischemic reperfusion 29 .…”