Dataset Information

Netrin-1 induces MMP-12-dependent E-cadherin degradation via the distinct activation of PKC? and FAK/Fyn in promoting mesenchymal stem cell motility.

ABSTRACT: Netrin-1 (Ntn-1) is a potent inducer of neuronal cell migration; however, its molecular mechanism that guides the migratory behavior of stem cells has not been characterized. In this study, we investigate the role of Ntn-1 in promoting the motility of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) and its related signaling pathways. Ntn-1 (50?ng/mL) significantly increased motility of UCB-MSCs, which was inhibited by blocking antibodies for deleted in colorectal cancer (DCC) and integrin (IN) ?6?4. Ntn-1 in DCC stimulated protein kinase C? (PKC?) activation, but not PKC?, PKC?, and PKC?, while Ntn-1 in IN?6?4 induced the phosphorylation of focal adhesion kinase (FAK) and Fyn. Notably, Ntn-1 induced phosphorylation of extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), and nuclear factor kappa-B (NF-?B), but they were concurrently downregulated by blocking the activities of PKC?, FAK, and Fyn. Ntn-1 uniquely increased the MMP-12 expression of all the matrix metalloproteinase (MMP) isoforms present in UCB-MSCs, though this was significantly blocked by an NF-?B inhibitor. Finally, Ntn-1 induced the MMP-12-dependent degradation of E-cadherin (E-cad), while Ntn-1 abrogated the interaction between E-cad and p120-catenin. In addition, Ntn-1 has the ability to stimulate cytoskeletal reorganization-related proteins, such as Cdc42, Rac1, Profilin-1, Cofilin-1, ?-Actinin-4, and filamentous actin (F-actin) in UCB-MSCs. These results demonstrate that Ntn-1 induces MMP-12-dependent E-cad degradation via the distinct activation of PKC? and FAK/Fyn, which is necessary to govern the activation of ERK, JNK, and NF-?B in promoting motility of UCB-MSCs.

SUBMITTER: Lee SJ

PROVIDER: S-EPMC4121046 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Netrin-1 induces MMP-12-dependent E-cadherin degradation via the distinct activation of PKCα and FAK/Fyn in promoting mesenchymal stem cell motility.

Lee Sei-Jung SJ Jung Young Hyun YH Oh Sang Yub SY Yong Min Sik MS Ryu Jung Min JM Han Ho Jae HJ

Stem cells and development 20140616 16

Netrin-1 (Ntn-1) is a potent inducer of neuronal cell migration; however, its molecular mechanism that guides the migratory behavior of stem cells has not been characterized. In this study, we investigate the role of Ntn-1 in promoting the motility of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) and its related signaling pathways. Ntn-1 (50 ng/mL) significantly increased motility of UCB-MSCs, which was inhibited by blocking antibodies for deleted in colorectal cancer (DCC ...[more]

PMID: 24738865

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Project description:BackgroundCadherin 12 (CDH12), which encodes a type II classical cadherin from the cadherin superfamily, may mediate calcium-dependent cell adhesion. It has been demonstrated that CDH12 could play an important role in the invasion and metastasis of salivary adenoid cystic carcinoma. We decided to investigate the relationship between CDH12 expression level and clinicopathologic variables in colorectal carcinoma (CRC) patients and to explore the functions of CDH12 in tumorigenesis in CRC.MethodsThe expression levels of CDH12 in colorectal carcinoma tissues were detected by immunohistochemistry. Real-time PCR and Western Blot were used to screen CDH12 high-expression cell lines. CCK-8 assay was used to detect the proliferation ability of CRC cells being transfected by shRNAs against CDH12. The wound assay and transwell assay were performed to test migration and invasion ability. The importance of CDH12 in cell-cell junctions was detected by cell adhesion assay and cell aggregation assay. Endothelial tube formation assay was used to test the influence of CDH12 on angiogenesis.ResultsStatistical analysis of clinical cases revealed that the positive rate of CDH12 was higher in the CRC tumor tissues compared with the adjacent non-tumor tissues. The expression levels of CDH12 in CRC patients are significantly correlated with invasion depth. Consistently, the ability of proliferation, migration and invasion were suppressed when CDH12 was decreased in CRC cells transfected with shRNAs. Cell adhesion assay and cell aggregation assay presented that tumor cells tend to disperse with the lack of CDH12. Endothelial tube formation assay showed that down-regulation of CDH12 could obviously inhibit the process of angiogenesis, implying that CDH12 may play an important role in tumor metastasisConclusionOur results showed that CDH12 promotes proliferation, migration, invasion, adhesion and angiogenesis, suggesting that CDH12 may be an oncogene in colorectal cancer. CDH12 is expected to become a new diagnostic and prognostic marker and a novel target of the treatment of colorectal cancer.

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Dataset Information

Netrin-1 induces MMP-12-dependent E-cadherin degradation via the distinct activation of PKC? and FAK/Fyn in promoting mesenchymal stem cell motility.

Publications

Netrin-1 induces MMP-12-dependent E-cadherin degradation via the distinct activation of PKCα and FAK/Fyn in promoting mesenchymal stem cell motility.

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