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MiR-21 enhances melanoma invasiveness via inhibition of tissue inhibitor of metalloproteinases 3 expression: in vivo effects of MiR-21 inhibitor

Metastatic melanoma is the most aggressive form of this cancer. It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement treatments for melanoma. Increased cell invasion through the extracellular matrix is required for me...

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Published in:PloS one 2015-01, Vol.10 (1), p.e0115919-e0115919
Main Authors: Martin del Campo, Sara E, Latchana, Nicholas, Levine, Kala M, Grignol, Valerie P, Fairchild, Ene T, Jaime-Ramirez, Alena Cristina, Dao, Thao-Vi, Karpa, Volodymyr I, Carson, Mary, Ganju, Akaansha, Chan, Anthony N, Carson, 3rd, William E
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cited_by cdi_FETCH-LOGICAL-c758t-d5ad41a4e101c16c6feccbedde708cfc9ce51dd08784adbd64343d991304ddb43
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container_title PloS one
container_volume 10
creator Martin del Campo, Sara E
Latchana, Nicholas
Levine, Kala M
Grignol, Valerie P
Fairchild, Ene T
Jaime-Ramirez, Alena Cristina
Dao, Thao-Vi
Karpa, Volodymyr I
Carson, Mary
Ganju, Akaansha
Chan, Anthony N
Carson, 3rd, William E
description Metastatic melanoma is the most aggressive form of this cancer. It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement treatments for melanoma. Increased cell invasion through the extracellular matrix is required for metastasis and is enhanced by matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits MMP activity. It was previously shown by our group that miR-21, a potential regulator of TIMP3, is over-expressed in cutaneous melanoma. It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21. Immunoblot analysis of miR-21-overexpressing cell lines revealed reduced expression of TIMP3 as compared to controls. This in turn led to a significant increase in the invasiveness of the radial growth phase cell line WM1552c and the vertical growth phase cell line WM793b (p < 0.05), but not in the metastatic cell lines A375 or MEL 39. The proliferation and migration of miR-21 over-expressing cell lines was not affected. Reduced expression of TIMP3 was achieved by siRNA knockdown and significantly enhanced invasion of melanoma cell lines, mimicking the effects of miR-21 over-expression. Treatment of tumor cells with a linked nucleic acid antagomir to miR-21 inhibited tumor growth and increased tumor expression of TIMP3 in vivo in 01B74 Athymic NCr-nu/nu mice. Intra-tumoral injections of anti-miR-21 produced similar effects. This data shows that increased expression of miR-21 enhanced the invasive potential of melanoma cell lines through TIMP3 inhibition. Therefore, inhibition of miR-21 in melanoma may reduce melanoma invasiveness.
doi_str_mv 10.1371/journal.pone.0115919
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It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement treatments for melanoma. Increased cell invasion through the extracellular matrix is required for metastasis and is enhanced by matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits MMP activity. It was previously shown by our group that miR-21, a potential regulator of TIMP3, is over-expressed in cutaneous melanoma. It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21. Immunoblot analysis of miR-21-overexpressing cell lines revealed reduced expression of TIMP3 as compared to controls. 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It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement treatments for melanoma. Increased cell invasion through the extracellular matrix is required for metastasis and is enhanced by matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits MMP activity. It was previously shown by our group that miR-21, a potential regulator of TIMP3, is over-expressed in cutaneous melanoma. It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21. Immunoblot analysis of miR-21-overexpressing cell lines revealed reduced expression of TIMP3 as compared to controls. This in turn led to a significant increase in the invasiveness of the radial growth phase cell line WM1552c and the vertical growth phase cell line WM793b (p &lt; 0.05), but not in the metastatic cell lines A375 or MEL 39. The proliferation and migration of miR-21 over-expressing cell lines was not affected. Reduced expression of TIMP3 was achieved by siRNA knockdown and significantly enhanced invasion of melanoma cell lines, mimicking the effects of miR-21 over-expression. Treatment of tumor cells with a linked nucleic acid antagomir to miR-21 inhibited tumor growth and increased tumor expression of TIMP3 in vivo in 01B74 Athymic NCr-nu/nu mice. Intra-tumoral injections of anti-miR-21 produced similar effects. This data shows that increased expression of miR-21 enhanced the invasive potential of melanoma cell lines through TIMP3 inhibition. Therefore, inhibition of miR-21 in melanoma may reduce melanoma invasiveness.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25587717</pmid><doi>10.1371/journal.pone.0115919</doi><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
ispartof PloS one, 2015-01, Vol.10 (1), p.e0115919-e0115919
issn 1932-6203
1932-6203
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source PubMed Central(OpenAccess); ProQuest Publicly Available Content database
subjects Biotechnology
Cancer
Cancer prevention
Cell Line, Tumor
Cell migration
Cell Movement - genetics
Cell Proliferation - genetics
Extracellular matrix
Gene Expression Regulation, Neoplastic
Humans
Inhibition
Inhibitors
Invasiveness
Matrix metalloproteinases
Melanoma
Melanoma - genetics
Melanoma - metabolism
Melanoma - pathology
Metastases
MicroRNAs - genetics
MicroRNAs - metabolism
Mimicry
Neoplasm Invasiveness - genetics
Neoplasm Invasiveness - pathology
Nucleic acids
Overexpression
RNA, Small Interfering
siRNA
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Skin Neoplasms - pathology
Tissue inhibitor of metalloproteinase 3
Tissue Inhibitor of Metalloproteinase-3 - genetics
Tissue Inhibitor of Metalloproteinase-3 - metabolism
Transfection
Tumor cells
title MiR-21 enhances melanoma invasiveness via inhibition of tissue inhibitor of metalloproteinases 3 expression: in vivo effects of MiR-21 inhibitor
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