Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

Abstract

The role of members of the insulin-like superfamily in human thyroid carcinoma is primarily unknown. Here we demonstrate the presence of RLN2 relaxin and relaxin receptor LGR7 in human papillary, follicular, and undifferentiated anaplastic thyroid carcinoma suggesting a specific involvement of relaxin-LGR7 signaling in thyroid carcinoma. Stable transfectants of the LGR7-positive human follicular thyroid carcinoma cell lines FTC-133 and FTC-238 that secrete bioactive proRLN2 revealed this hormone to act as a multifunctional endocrine factor in thyroid carcinoma cells. Although RLN2 did not act as a mitogen, it acted as an autocrine/paracrine factor and significantly increased anchorage-independent growth and thyroid carcinoma cell motility and invasiveness through elastin matrices. In recent years, the multifunctional peptide hormone relaxin has been identified as an important endocrine player in the reproductive tract, cardiovascular/neural systems, and oncology.1,2 The thyroid was once considered to be a relaxin target tissue with relaxin reported to increase thyroid weight, radioactive iodine uptake, and protein-bound iodination in rats.3,4 Likely because of the crude relaxin preparations used at the time, these results could not be confirmed. 5 No further investigations were reported thereafter using highly purified relaxin preparations to validate a potential role of relaxin in thyroid tissues and thyroid cell lines. Some 40 years later, the discovery of the G-protein-coupled relaxin-like receptors LGR7 and LGR8 revealed the presence of transcripts for both LGR7 (relaxin receptor) and LGR8 (INSL3/relaxin receptor) in the thyroid gland. 6 -8 Relaxin and the relaxin-like INSL3 have been shown to activate cAMP-dependent signaling pathways by binding to either LGR7 or LGR8. 8 -12 We recently demonstrated the expression and regulation of INSL3 and LGR8 transcripts in human thyroid carcinoma cell lines, identifying hyper-and neoplastic human thyrocytes as a new source and target of the actions of INSL3 and a novel INSL3 splice variant. 8,13 Although still primarily undefined, relaxin appears to have oncogenic potential in various organs and tissues, including the human thyroid.14 -17 Relaxin affects proliferation and differentiation of MCF-7 human carcinoma cells in a concentration-dependent manner 18 and can modify the extracellular matrix by affecting the expresSupported by the Deutsche Forschungsgemeinschaft (grants KL1249/5-1

Relaxin Enhances S100A4 and Promotes Growth of Human Thyroid Carcinoma Cell Xenografts

“…Relaxin (RLN2) confers increased carcinoma cell motility and in vitro invasiveness in human thyroid carcinoma cells and this process is mediated by the relaxin receptor, relaxin family peptide receptor 1 (RXFP1; ref. 10). Furthermore, we showed that in human thyroid carcinoma cells, the enhanced migration through elastin matrices was mediated as a result of relaxin-induced increase in the production and secretion of elastinolytic cathepsin-L (10).…”

“…10). Furthermore, we showed that in human thyroid carcinoma cells, the enhanced migration through elastin matrices was mediated as a result of relaxin-induced increase in the production and secretion of elastinolytic cathepsin-L (10).…”

“…TT2609-C02 was cultivated in RPMI supplemented with 1.125 g/L sodium carbonate, 20% FCS, 1% sodium pyruvate (SigmaAldrich), and 1% insulin-transferrin-selentite (Invitrogen). Stable FTC133-pIRES-EGFP-RLN2 and FTC133-pIRES-EGFP vector control transfectans were previously described (10). C643-pcDNA4HisMax (C643-HisMax) and C643-S100A4 in pcDNA4HisMax (C643-S100A4) stable transfectants were selected and cultured with 100 μg/mL Zeocin (Invitrogen).…”

“…We have previously shown that the polypeptide hormone relaxin is expressed exclusively in human thyroid carcinoma but not in benign thyroid conditions (10). Relaxin (RLN2) confers increased carcinoma cell motility and in vitro invasiveness in human thyroid carcinoma cells and this process is mediated by the relaxin receptor, relaxin family peptide receptor 1 (RXFP1; ref.…”

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

“…CTRP8‐activated RXFP1 may utilize PI3K to mediate STAT3 activation as PI3K and its target BMX TEC kinase were recently shown to mediate the phosphorylation of STAT3 (Glogowska et al ., 2013; Hart et al ., 2011). We also previously identified lysosomal cathepsins as targets of H2 relaxin, the cognate ligand of RXFP1, and CTRP8 in human thyroid cancer (cathepsin‐D and cathepsin‐L) and GBM (cathepsin‐B), respectively (Glogowska et al ., 2013; Hombach‐Klonisch et al ., 2006). High cathepsin‐B serum levels are associated with poor prognosis in GBM patients (Strojnik et al ., 2005).…”