miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations
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miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations. / Thomsen, Karina G; Terp, Mikkel G; Lund, Rikke R; Søkilde, Rolf; Elias, Daniel; Bak, Martin; Litman, Thomas; Beck, Hans C; Lyng, Maria B; Ditzel, Henrik J.
In: OncoTarget, Vol. 6, No. 30, 06.10.2015, p. 29224-39.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations
AU - Thomsen, Karina G
AU - Terp, Mikkel G
AU - Lund, Rikke R
AU - Søkilde, Rolf
AU - Elias, Daniel
AU - Bak, Martin
AU - Litman, Thomas
AU - Beck, Hans C
AU - Lyng, Maria B
AU - Ditzel, Henrik J
PY - 2015/10/6
Y1 - 2015/10/6
N2 - To gain insight into miRNA regulation in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using global miRNA profiling, 28 miRNAs were found to exhibit significantly altered expression between isogenic metastasizing and non-metastasizing cancer cells, with miR-155 being the most differentially expressed. Highly metastatic mesenchymal-like CL16 cancer cells showed very low miR-155 expression, and miR-155 overexpression in these cells lead to significantly decreased tumor burden in lungs when injected intravenously in immunodeficient mice. Our experiments addressing the underlying mechanism of the altered tumor burden revealed that miR-155-overexpressing CL16 cells were less invasive than CL16 control cells in vitro, while miR-155 overexpression had no effect on cancer cell proliferation or apoptosis in established lung tumors. To identify proteins regulated by miR-155 and thus delineate its function in our cell model, we compared the proteome of xenograft tumors derived from miR-155-overexpressing CL16 cells and CL16 control cells using mass spectrometry-based proteomics. >4,000 proteins were identified, of which 92 were consistently differentially expressed. Network analysis revealed that the altered proteins were associated with cellular functions such as movement, growth and survival as well as cell-to-cell signaling and interaction. Downregulation of the three metastasis-associated proteins ALDH1A1, PIR and PDCD4 in miR-155-overexpressing tumors was validated by immunohistochemistry. Our results demonstrate that miR-155 inhibits the ability of cancer cells to extravasate and/or colonize at distant organs and brings additional insight into the complexity of miR-155 regulation in metastatic seeding.
AB - To gain insight into miRNA regulation in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using global miRNA profiling, 28 miRNAs were found to exhibit significantly altered expression between isogenic metastasizing and non-metastasizing cancer cells, with miR-155 being the most differentially expressed. Highly metastatic mesenchymal-like CL16 cancer cells showed very low miR-155 expression, and miR-155 overexpression in these cells lead to significantly decreased tumor burden in lungs when injected intravenously in immunodeficient mice. Our experiments addressing the underlying mechanism of the altered tumor burden revealed that miR-155-overexpressing CL16 cells were less invasive than CL16 control cells in vitro, while miR-155 overexpression had no effect on cancer cell proliferation or apoptosis in established lung tumors. To identify proteins regulated by miR-155 and thus delineate its function in our cell model, we compared the proteome of xenograft tumors derived from miR-155-overexpressing CL16 cells and CL16 control cells using mass spectrometry-based proteomics. >4,000 proteins were identified, of which 92 were consistently differentially expressed. Network analysis revealed that the altered proteins were associated with cellular functions such as movement, growth and survival as well as cell-to-cell signaling and interaction. Downregulation of the three metastasis-associated proteins ALDH1A1, PIR and PDCD4 in miR-155-overexpressing tumors was validated by immunohistochemistry. Our results demonstrate that miR-155 inhibits the ability of cancer cells to extravasate and/or colonize at distant organs and brings additional insight into the complexity of miR-155 regulation in metastatic seeding.
KW - Aldehyde Dehydrogenase/genetics
KW - Animals
KW - Apoptosis Regulatory Proteins/genetics
KW - Biomarkers, Tumor/genetics
KW - Carrier Proteins/genetics
KW - Cell Line, Tumor
KW - Cell Movement
KW - Cell Proliferation
KW - Female
KW - Gene Expression Profiling/methods
KW - Gene Expression Regulation, Neoplastic
KW - Genetic Predisposition to Disease
KW - Humans
KW - Immunohistochemistry
KW - Lung Neoplasms/genetics
KW - Mass Spectrometry
KW - Mice
KW - Mice, SCID
KW - MicroRNAs/genetics
KW - Nuclear Proteins/genetics
KW - Oligonucleotide Array Sequence Analysis
KW - Phenotype
KW - Protein Interaction Maps
KW - Proteomics/methods
KW - RNA-Binding Proteins/genetics
KW - Signal Transduction
KW - Time Factors
KW - Transfection
U2 - 10.18632/oncotarget.4942
DO - 10.18632/oncotarget.4942
M3 - Journal article
C2 - 26317550
VL - 6
SP - 29224
EP - 29239
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 30
ER -
ID: 200580434