title: Relaxin enhances the collagenolytic activity and in vitro invasiveness by upregulating matrix metalloproteinases in human thyroid carcinoma cells.
abstract: In this study, we identified differential expression of immunoreactive matrix metalloproteinase 2 (MMP2)/gelatinase A, membrane-anchored MT1-MMP/MMP14, and human relaxin-2 (RLN2) in human benign and malignant thyroid tissues. MMP2 and MT1-MMP were detected in the majority of thyroid cancer tissues and colocalized with RLN2-positive cells. MMP2 was mostly absent in goiter tissues and, similar to RLN2, may serve as a marker for thyroid cancer. MMP2 and MT1-MMP were identified as novel RLN2 targets. RLN2 caused a significant downregulation of tissue inhibitor of MMP (TIMP) 3 protein levels but did not change the expression levels of MMP13, and TIMP1, TIMP2, and TIMP4 in human thyroid carcinoma cells. RLN2 failed to affect the expression of MMP1, 3, 8, and 9 in the thyroid carcinoma cells investigated. Stable RLN2 transfectants secreted enhanced levels of bioactive MMP2 which contributed to the increased collagenolytic activity and in vitro invasiveness into collagen matrix by human thyroid cancer cells. Three-dimensional reconstitution of confocal fluorescent microscopy images revealed larger-sized invadopodia, with intense MT1-MMP accumulation at the leading migrating edge in RLN2 transfectants when compared with enhanced green fluorescent protein clones. In RLN2 transfectants actin stress fibers contributed to pseudopodia formation. In conclusion, enhanced tumor cell invasion by RLN2 involves the formation of MT1-MMP-enriched invadopodia that lead to increased collagenolytic cell invasion by human thyroid cancer cells.
authors.affiliation: Clinics of General, Visceral and Vascular Surgery, Martin Luther University, Halle (Saale), Saxony-Anhalt, Germany.
authors.forename: Joanna
authors.initials: J
authors.lastname: Bialek
authors.forename: Usakorn
authors.initials: U
authors.lastname: Kunanuvat
authors.forename: Sabine
authors.initials: S
authors.lastname: Hombach-Klonisch
authors.forename: Antje
authors.initials: A
authors.lastname: Spens
authors.forename: Joerg
authors.initials: J
authors.lastname: Stetefeld
authors.forename: Kevin
authors.initials: K
authors.lastname: Sunley
authors.forename: Dustin
authors.initials: D
authors.lastname: Lippert
authors.forename: John A
authors.initials: JA
authors.lastname: Wilkins
authors.forename: Cuong
authors.initials: C
authors.lastname: Hoang-Vu
authors.forename: Thomas
authors.initials: T
authors.lastname: Klonisch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002465:Cell Movement; D002648:Child; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006042:Goiter / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011554:Pseudopodia / Q000378:metabolism; D012065:Relaxin / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000473:pathology*
chemical_list: C095068:RLN2 protein, human; D012065:Relaxin; D003094:Collagen; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14