The Collagen-Modifying Enzyme PLOD2 Is Induced and Required during L1-Mediated Colon Cancer Progression
| Autor: | Sanith Cheriyamundath, Nancy Gavert, Avri Ben-Ze'ev, Anmol Kumar, Thomas Brabletz |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Smad2 Protein medicine.disease_cause Metastasis lcsh:Chemistry Small hairpin RNA Transactivation 0302 clinical medicine Ezrin Cell Movement Intestinal Mucosa lcsh:QH301-705.5 Spectroscopy Cell adhesion molecule Chemistry Procollagen-Lysine 2-Oxoglutarate 5-Dioxygenase Liver Neoplasms Wnt signaling pathway General Medicine Transfection L1 Computer Science Applications Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Colonic Neoplasms colonic crypts Collagen lysyl hydroxylase 2 Mice Nude Neural Cell Adhesion Molecule L1 colorectal cancer Catalysis Article Inorganic Chemistry 03 medical and health sciences Cell Line Tumor medicine Animals ddc:610 Smad3 Protein Physical and Theoretical Chemistry Molecular Biology PLOD2 Organic Chemistry medicine.disease Xenograft Model Antitumor Assays invasion and metastasis ezrin Cytoskeletal Proteins 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 Cancer research Carcinogenesis |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 7 International Journal of Molecular Sciences, Vol 22, Iss 3552, p 3552 (2021) |
| ISSN: | 1422-0067 |
| Popis: | The overactivation of Wnt/β-catenin signaling is a hallmark of colorectal cancer (CRC) development. We identified the cell adhesion molecule L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. The overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis and liver metastasis, and L1 is exclusively localized in the invasive areas of human CRC tissue. A number of genes are induced after L1 transfection into CRC cells by a mechanism involving the cytoskeletal protein ezrin and the NF-κB pathway. When studying the changes in gene expression in CRC cells overexpressing L1 in which ezrin levels were suppressed by shRNA to ezrin, we discovered the collagen-modifying enzyme lysyl hydroxylase 2 (PLOD2) among these genes. We found that increased PLOD2 expression was required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis and liver metastasis, since the suppression of endogenous PLOD2 expression, or its enzymatic activity, blocked the enhanced tumorigenic properties conferred by L1. The mechanism involved in increased PLOD2 expression by L1 involves ezrin signaling and PLOD2 that affect the SMAD2/3 pathway. We found that PLOD2 is localized in the colonic crypts in the stem cell compartment of the normal mucosa and is found at increased levels in invasive areas of the tumor and, in some cases, throughout the tumor tissue. The therapeutic strategies to target PLOD2 expression might provide a useful approach for CRC treatment. |
| Databáze: | OpenAIRE |
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