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Epigenetic Silencing of SPINT2 promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma
Aberrant HGF-MET signaling activation via interactions with surrounding stromal cells in tumor microenvironment plays significant roles in malignant tumor progression. However, extracellular proteolytic regulation of HGF activation which is influenced by the tumor microenvironment and its consequent...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537358/ https://www.ncbi.nlm.nih.gov/pubmed/25910030 http://dx.doi.org/10.1038/jid.2015.160 |
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author | Hwang, Soonyean Kim, Hye-Eun Min, Michelle Raghunathan, Rekha Panova, Izabela P. Munshi, Ruchi Ryu, Byungwoo |
author_facet | Hwang, Soonyean Kim, Hye-Eun Min, Michelle Raghunathan, Rekha Panova, Izabela P. Munshi, Ruchi Ryu, Byungwoo |
author_sort | Hwang, Soonyean |
collection | PubMed |
description | Aberrant HGF-MET signaling activation via interactions with surrounding stromal cells in tumor microenvironment plays significant roles in malignant tumor progression. However, extracellular proteolytic regulation of HGF activation which is influenced by the tumor microenvironment and its consequential effects on melanoma malignancy remain uncharacterized. In this study we identified SPINT2: a proteolytic inhibitor of hepatocyte growth factor activator (HGFA), which plays a significant role in the suppression of the HGF-MET pathway and malignant melanoma progression. SPINT2 expression is significantly lower in metastatic melanoma tissues compared to those in early stage primary melanomas which also corresponded with DNA methylation levels isolated from tissue samples. Treatment with the DNA hypomethylating agent decitabine in cultured melanoma cells induced transcriptional reactivation of SPINT2, suggesting that this gene is epigenetically silenced in malignant melanomas. Furthermore, we show that ectopically expressed SPINT2 in melanoma cells inhibits HGF induced MET-AKT signaling pathway and decreases malignant phenotype potential such as cell motility, and invasive growth of melanoma cells. These results suggest that SPINT2 is associated with tumor suppressive functions in melanoma by inhibiting an extracellular signal regulator of HGF which is typically activated by tumor-stromal interactions. These findings indicate that epigenetic impairment of the tightly regulated cytokine-receptor communications in tumor microenvironment may contribute to malignant tumor progression. |
format | Online Article Text |
id | pubmed-4537358 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-45373582016-03-01 Epigenetic Silencing of SPINT2 promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma Hwang, Soonyean Kim, Hye-Eun Min, Michelle Raghunathan, Rekha Panova, Izabela P. Munshi, Ruchi Ryu, Byungwoo J Invest Dermatol Article Aberrant HGF-MET signaling activation via interactions with surrounding stromal cells in tumor microenvironment plays significant roles in malignant tumor progression. However, extracellular proteolytic regulation of HGF activation which is influenced by the tumor microenvironment and its consequential effects on melanoma malignancy remain uncharacterized. In this study we identified SPINT2: a proteolytic inhibitor of hepatocyte growth factor activator (HGFA), which plays a significant role in the suppression of the HGF-MET pathway and malignant melanoma progression. SPINT2 expression is significantly lower in metastatic melanoma tissues compared to those in early stage primary melanomas which also corresponded with DNA methylation levels isolated from tissue samples. Treatment with the DNA hypomethylating agent decitabine in cultured melanoma cells induced transcriptional reactivation of SPINT2, suggesting that this gene is epigenetically silenced in malignant melanomas. Furthermore, we show that ectopically expressed SPINT2 in melanoma cells inhibits HGF induced MET-AKT signaling pathway and decreases malignant phenotype potential such as cell motility, and invasive growth of melanoma cells. These results suggest that SPINT2 is associated with tumor suppressive functions in melanoma by inhibiting an extracellular signal regulator of HGF which is typically activated by tumor-stromal interactions. These findings indicate that epigenetic impairment of the tightly regulated cytokine-receptor communications in tumor microenvironment may contribute to malignant tumor progression. 2015-04-24 2015-09 /pmc/articles/PMC4537358/ /pubmed/25910030 http://dx.doi.org/10.1038/jid.2015.160 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Hwang, Soonyean Kim, Hye-Eun Min, Michelle Raghunathan, Rekha Panova, Izabela P. Munshi, Ruchi Ryu, Byungwoo Epigenetic Silencing of SPINT2 promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma |
title | Epigenetic Silencing of SPINT2 promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma |
title_full | Epigenetic Silencing of SPINT2 promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma |
title_fullStr | Epigenetic Silencing of SPINT2 promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma |
title_full_unstemmed | Epigenetic Silencing of SPINT2 promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma |
title_short | Epigenetic Silencing of SPINT2 promotes Cancer Cell Motility via HGF-MET Pathway Activation in Melanoma |
title_sort | epigenetic silencing of spint2 promotes cancer cell motility via hgf-met pathway activation in melanoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537358/ https://www.ncbi.nlm.nih.gov/pubmed/25910030 http://dx.doi.org/10.1038/jid.2015.160 |
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