Abstract
De-regulated EFEMP1 gene expression in solid tumors has been widely reported with conflicting roles. We dissected EFEMP1 to identify domains responsible for its cell context-dependent dual functions, with the goal being to construct an EFEMP1-derived tumor-suppressor protein (ETSP) that lacked tumor-promoting function. Exon/intron boundaries of EFEMP1 were used as boundaries of functional modules in constructing EFEMP1 variants, with removal of various module(s), and/or mutating an amino acid residue to convert a weak integrin binding-site into a strong one. A series of in vitro assays on cancerous features, and subcutaneous and intracranial xenograft-formation assays, were carried out for effects from overexpression of wild-type and variant forms of EFEMP1 in two glioma subpopulations characterized as tumor mass-forming cells (TMCs) or stem-like tumor initiating cells (STICs), where EFEMP1 showed cellcontext- dependent dual functions. One of the EFEMP1 variants was identified as the sought-after ETSP, which had a stronger tumor-suppression function in TMCs by targeting EGFR and angiogenesis, and a new tumor-suppression function in STICs by targeting NOTCH signaling and MMP2-mediated cell invasion. Therefore, ETSP may form the basis for further important research to develop a novel cancer therapy to treat many types of cancer by its tumor suppressor effect in the extracellular matrix compartment.
Highlights
Fibulins are secreted glycoproteins that contain a series of epidermal growth factor (EGF)-like modules followed by a carboxy-terminal fibulin-type module, and function as intramolecular bridges within the extracellular matrix that mediate cellular processes and tissue remodeling
We report in this study the identification of such an EFEMP1-derived tumor-suppressor protein (ETSP) from fourteen expression constructs of EFEMP1 having a deletion and/or mutation, based on effects generated from their over-expression, in vitro and in vivo, in two syngeneic glioma cell lines
The EGFR-homologous region (EHR) of EFEMP1 was aligned to the extracellular region of EGFR of all four isoforms of EGFR and an EGFR deletion mutant EGFRvIII (Figure 1A)
Summary
Fibulins are secreted glycoproteins that contain a series of epidermal growth factor (EGF)-like modules followed by a carboxy-terminal fibulin-type module, and function as intramolecular bridges within the extracellular matrix that mediate cellular processes and tissue remodeling. EFEMP1 (known as fibulin 3) is a fibulin of recent evolutionary origin in higher vertebrates It was initially identified as a senescence protein [4, 5], and recently was widely reported in most kinds of cancer to have deregulated expression, mainly via promoter hyper-methylations that correlated with its anti-cancer effect (see review in [6]). The anti-tumor effects of EFEMP1 in most cancer types are most likely accounted for by its anti-angiogenic effect [7], its anti-EGFR/AKT-mediated growth signaling effect [8,9,10,11], and its anti-IGF1R [12] and/or anti-TGFbeta [13] mediated epithelial-to-mesenchymal transition effects, as well as its function in normal tissue to inhibit www.impactjournals.com/oncoscience the expression and activities of matrix metalloproteinase [14]. Our recent studies have shown that both types of EFEMP1 roles operate in a cell-context-dependent manner in two tumor-cell subpopulations with differential activation of EGFR or NOTCH signaling, which stabilized the cell subpopulation equilibrium in responses to changes of the in vivo growth environment [17]
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