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Ectodomain shedding of T?RIII is required for T?RIII-mediated suppression of TGF-? signaling and breast cancer migration and invasion.

ABSTRACT: The type III transforming growth factor ? (TGF-?) receptor (T?RIII), also known as betaglycan, is the most abundantly expressed TGF-? receptor. T?RIII suppresses breast cancer progression by inhibiting migration, invasion, metastasis, and angiogenesis. T?RIII binds TGF-? ligands, with membrane-bound T?RIII presenting ligand to enhance TGF-? signaling. However, T?RIII can also undergo ectodomain shedding, releasing soluble T?RIII, which binds and sequesters ligand to inhibit downstream signaling. To investigate the relative contributions of soluble and membrane-bound T?RIII on TGF-? signaling and breast cancer biology, we defined T?RIII mutants with impaired (?Shed-T?RIII) or enhanced ectodomain shedding (SS-T?RIII). Inhibiting ectodomain shedding of T?RIII increased TGF-? responsiveness and abrogated T?RIII's ability to inhibit breast cancer cell migration and invasion. Conversely, expressing SS-T?RIII, which increased soluble T?RIII production, decreased TGF-? signaling and increased T?RIII-mediated inhibition of breast cancer cell migration and invasion. Of importance, SS-T?RIII-mediated increases in soluble T?RIII production also reduced breast cancer metastasis in vivo. Taken together, these studies suggest that the ratio of soluble T?RIII to membrane-bound T?RIII is an important determinant for regulation of T?RIII- and TGF-?-mediated signaling and biology.

SUBMITTER: Elderbroom JL

PROVIDER: S-EPMC4142606 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion.

Elderbroom Jennifer L JL Huang Jennifer J JJ Gatza Catherine E CE Chen Jian J How Tam T Starr Mark M Nixon Andrew B AB Blobe Gerard C GC

Molecular biology of the cell 20140625 16

The type III transforming growth factor β (TGF-β) receptor (TβRIII), also known as betaglycan, is the most abundantly expressed TGF-β receptor. TβRIII suppresses breast cancer progression by inhibiting migration, invasion, metastasis, and angiogenesis. TβRIII binds TGF-β ligands, with membrane-bound TβRIII presenting ligand to enhance TGF-β signaling. However, TβRIII can also undergo ectodomain shedding, releasing soluble TβRIII, which binds and sequesters ligand to inhibit downstream signaling. ...[more]

PMID: 24966170

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Project description:BackgroundColorectal cancer (CRC) is an aggressive tumor of the gastrointestinal tract, which is a major public health concern worldwide. Despite numerous studies, the precise mechanism of metastasis behind its progression remains elusive. As a member of the containing olfactomedin domains protein family, olfactomedin 2 (OLFM2) may play a role in tumor metastasis. It is highly expressed in colorectal cancer, and its role in the metastasis of CRC is still unclear. As such, this study seeks to explore the function of OLFM2 on CRC metastasis and its potential mechanisms.MethodsReal-time fluorescence quantitative PCR and western blotting were used to study the expression of OLFM2 in human CRC and adjacent normal tissues. Knockdown and overexpression OLFM2 cell lines were constructed using siRNA and overexpression plasmids to explore the role of OLFM2 in the migration and invasion of CRC through transwell, and wound healing experiments. Finally, the expression of epithelial-mesenchymal transition (EMT) -related proteins and TGF-β/Smad signaling pathway-related proteins was investigated using western blotting.ResultsIn this study, we observed an elevation of OLFM2 expression levels in CRC tissues. To investigate the function of OLFM2, we overexpressed and knocked down OLFM2. We discovered that OLFM2 knockdown inhibited migration and invasion of colon cancer cells. Furthermore, E-cadherin expression increased while N-cadherin and Vimentin expression were opposite. It is no surprise that overexpressing OLFM2 had the opposite effects. We also identified that OLFM2 knockdown resulted in reduced TGF-βR1 and downstream molecules p-Smad2 and p-Smad3, which are related to the TGF-β / Smad pathway. In contrast, overexpressing OLFM2 significantly boosted their expression levels.ConclusionThe protein OLFM2 has been identified as a crucial determinant in the progression of CRC. Its mechanism of action involves the facilitation of EMT through the TGF-β/Smad signaling pathway. Given its pivotal role in CRC, OLFM2 has emerged as a promising diagnostic and therapeutic target for the disease. These results indicate the potential of OLFM2 as a valuable biomarker for CRC diagnosis and treatment and highlight the need for further research exploring its clinical significance.

Dataset Information

Ectodomain shedding of T?RIII is required for T?RIII-mediated suppression of TGF-? signaling and breast cancer migration and invasion.

Publications

Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion.

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