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RECK: a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling
Makoto Noda1, Junseo Oh, Rei Takahashi
1Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. mnoda@virus.kyoto-v.ac.jp
Abstract:
RECK was first isolated as a transformation suppressor gene by cDNA expression cloning in a mouse fibroblast cell line transformed by an activated RAS oncogene. Subsequently, reduced expression of RECK in transformed cells and cancer cells were demonstrated. Moreover, in several types of tumors, positive correlation between RECK expression and survival of patients have been noted. RECK encodes a GPI-anchored glycoprotein harboring three protease inhibitor-like domains. The RECK protein regulates at least three members of the matrix metalloproteinase (MMP) family, MMP-2, MMP-9, and MT1-MMP, in vitro or in cultured cells. Restored expression of RECK in cancer cell lines results in strong suppression of invasion, metastasis, and tumor angiogenesis. Mice lacking RECK die in utero with reduced integrity of blood vessels, the neural tube, and mesenchymal tissues. In these mice, MMP activity is elevated, and the amount of collagen type I greatly reduced. The RECK null phenotype is partially rescued (half day delay of death and marked recovery of tissue integrity) by MMP-2 null mutation, demonstrating functional interaction between RECK and MMP-2 in vivo and involvement of other target(s) for RECK in the lethal phenotype. These findings indicate that (i) RECK is an important regulator of extracellular matrix remodeling and that (ii) down-regulation of RECK by oncogenic signaling leads to the excessive activation of MMPs thereby promoting malignant behavior of cancer cells such as invasion, metastasis, and angiogenesis.
Insights
RECK, a tumor suppressor gene, regulates extracellular matrix remodeling by controlling matrix metalloproteinases (MMPs). Its loss promotes cancer invasion and metastasis.
Area of Science:
- Molecular Biology
- Cancer Research
- Developmental Biology
Background:
- RECK (Reversion-inducing cysteine-rich protein with kazal motifs) was identified as a transformation suppressor gene.
- Reduced RECK expression is observed in cancer cells, correlating with poorer patient survival.
- RECK encodes a GPI-anchored glycoprotein involved in regulating matrix metalloproteinases (MMPs).
Purpose of the Study:
- To investigate the role of RECK in extracellular matrix remodeling and cancer progression.
- To elucidate the in vivo function of RECK and its interaction with MMPs.
- To understand how oncogenic signaling affects RECK expression and contributes to malignancy.
Main Methods:
- cDNA expression cloning to identify RECK.
- Analysis of RECK expression in cancer cell lines and patient tumors.
- Functional studies in RECK-deficient mice and MMP-2 knockout mice.
- In vitro assays to assess RECK's regulation of MMPs (MMP-2, MMP-9, MT1-MMP).
Main Results:
- Restored RECK expression suppressed cancer cell invasion, metastasis, and angiogenesis.
- RECK-deficient mice exhibited embryonic lethality with vascular and tissue integrity defects.
- Elevated MMP activity and reduced collagen type I were observed in RECK-null mice.
- MMP-2 deficiency partially rescued the RECK-null phenotype, indicating functional interaction.
Conclusions:
- RECK is a critical regulator of extracellular matrix remodeling.
- Downregulation of RECK by oncogenic signaling promotes excessive MMP activation, driving cancer invasion, metastasis, and angiogenesis.
- RECK plays a vital role in maintaining tissue integrity during development.