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. Mol Cancer Res; 9(6); 673-87. Ó2011 AACR.

C1q‐tumour necrosis factor‐related protein 8 (CTRP8) is a novel interaction partner of relaxin receptor RXFP1 in human brain cancer cells

“…RLN2‐mediated RXFP1 activation contributes to tissue invasion and metastasis of tumour cells in several ways. This involves the up‐regulation of the motility‐enhancing calcium‐binding protein S100A4, also known as metastasin or Mts1 , and proteolytic effector pathways, including the matrix‐metalloproteinases (MMPs) collagenase 1 (MMP1) and 3 (MMP13), gelatinase A (MMP2) and B (MMP9), stromelysin 1 (MMP3), MT1‐MMP (MMP14), and tissue inhibitors of MMP (TIMP3) in human breast and thyroid cancer . Among the family of lysosomal hydrolases of the cathepsin (cath) family, we identified cathB, cathL, and cathD as important relaxin targets that facilitate extracellular matrix (ECM) degradation by human thyroid cancer cells .…”

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

“…In patients with prostate cancer, elevated relaxin levels are linked to cancer progression, metastasis, and androgen independence . Likewise, relaxin heightens the collagenolytic potency of thyroid cancer cells by upregulating MMP-2 that facilitates greater in vitro invasiveness (Bialek et al, 2011). In human osteosarcoma cells, relaxin promotes faster in vitro growth, invasion, and angiogenesis via the Akt and VEGF pathways, and small interfering RNA-mediated knockdown of relaxin greatly mitigates these effects (Ma et al, 2013a,b).…”

Relaxin 2 – a pregnancy hormone involved in the process of carcinogenesis

“…Relaksyna 2 odgrywa ważną rolę w remodelingu macierzy zewnątrzkomórkowej wielu tkanek reprodukcyjnych. Stymuluje przebudowę tkanki łącznej poprzez hamowanie syntezy kolagenu i wzrost ekspresji i aktywacji MMPs [31][32][33][34]. Metaloproteinazy, główne enzymy zdolne do degradacji błony podstawnej i składników macierzy pozakomórkowej, uwalniane są w postaci nieaktywnego proenzymu.…”

“…Aktywacja MMPs obejmuje: odszczepienie cysteiny z fragmentu enzymu, zmiany konformacyje, odcięcie N-końcowego odcinka tak, aby odsłonić miejsce aktywne z atomem cynku [29]. Wpływ relaksyny 2 na MMP/TIMP system jest tkankowo-komórkowo zależny [31][32][33][34][35].…”