miR-19-Mediated Inhibition of Transglutaminase-2 Leads to Enhanced Invasion and Metastasis in Colorectal Cancer.
Transglutaminase-2 (TG2) is a critical cross-linking enzyme in the extracellular matrix (ECM) and tumor microenvironment (TME). Although its expression has been linked to colorectal cancer, its functional role in the processes that drive disease appears to be context dependent. There is now considerable evidence of a role for microRNAs (miRNA) in the development and progression of cancer, including metastasis. A cell model of metastatic colon adenocarcinoma was used to investigate the contribution of miRNAs to the differential expression of TG2, and functional effects on inflammatory and invasive behavior. The impact of TG2 in colorectal cancer was analyzed in human colorectal tumor specimens and by manipulations in SW480 and SW620 cells. Effects on invasive behavior were measured using Transwell invasion assays, and cytokine production was assessed by ELISA. TG2 was identified as a target for miR-19 by in silico analysis, which was confirmed experimentally. Functional effects were evaluated by overexpression of pre-miR-19a in SW480 cells. Expression of TG2 correlated inversely with invasive behavior, with knockdown in SW480 cells leading to enhanced invasion, and overexpression in SW620 cells the opposite. TG2 expression was observed in colorectal cancer primary tumors but lost in liver metastases. Finally, miR-19 overexpression and subsequent decreased TG2 expression was linked to chromosome-13 amplification events, leading to altered invasive behavior in colorectal cancer cells.


CONCLUSIONS
Chromosome-13 amplification in advanced colorectal cancer contributes to invasion and metastasis by upregulating miR-19, which targets TG2.
Molecular mechanisms research unit, Cancer Research UK Centre, University of Southampton Cancer Sciences Division, Somers Cancer Research Building, Southampton University Hospital NHS Trust, Tremona road, Southampton, SO16 6YD.
D
D
Cellura
Molecular mechanisms research unit, Cancer Research UK Centre, University of Southampton Cancer Sciences Division, Somers Cancer Research Building, Southampton University Hospital NHS Trust, Tremona road, Southampton, SO16 6YD.
K
K
Pickard
Molecular mechanisms research unit, Cancer Research UK Centre, University of Southampton Cancer Sciences Division, Somers Cancer Research Building, Southampton University Hospital NHS Trust, Tremona road, Southampton, SO16 6YD.
S
S
Quaratino
Cancer Genomics, Cancer Sciences, University of Southampton, Southampton, SO16 6YD.
H
H
Parker
Cancer Genomics, Cancer Sciences, University of Southampton, Southampton, SO16 6YD.
J C
JC
Strefford
Molecular mechanisms research unit, Cancer Research UK Centre, University of Southampton Cancer Sciences Division, Somers Cancer Research Building, Southampton University Hospital NHS Trust, Tremona road, Southampton, SO16 6YD.
G J
GJ
Thomas
Bioinformatics Unit, London Research Institute, Cancer Research UK, Lincoln's Inn Fields, London, WC2A 3TL.
R
R
Mitter
Molecular mechanisms research unit, Cancer Research UK Centre, University of Southampton Cancer Sciences Division, Somers Cancer Research Building, Southampton University Hospital NHS Trust, Tremona road, Southampton, SO16 6YD.|Department of Colorectal Surgery, Southampton University Hospital NHS Trust, Tremona road, Southampton, UK.
A H
AH
Mirnezami
Molecular mechanisms research unit, Cancer Research UK Centre, University of Southampton Cancer Sciences Division, Somers Cancer Research Building, Southampton University Hospital NHS Trust, Tremona road, Southampton, SO16 6YD.
N J
NJ
Peake
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008113:Liver Neoplasms / Q000556:secondary*; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000378:metabolism*
D016207:Cytokines; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins