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(American Journal of Pathology. 2006;169:617-632.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.050876

Relaxin Enhances the Oncogenic Potential of Human Thyroid Carcinoma Cells

Sabine Hombach-Klonisch*{dagger}, Joanna Bialek{ddagger}, Bogusz Trojanowicz{ddagger}, Ekkehard Weber§, Hans-Jürgen Holzhausen, Josh D. Silvertown||, Alastair J. Summerlee**, Henning Dralle{ddagger}, Cuong Hoang-Vu{ddagger} and Thomas Klonisch*{dagger}{dagger}

From the Departments of Human Anatomy and Cell Science,* Obstetrics, Gynecology, and Reproductive Sciences,{dagger} and Medical Microbiology,{dagger}{dagger} University of Manitoba, Winnipeg, Manitoba, Canada; the Division of Stem Cell and Developmental Biology,|| Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada; Biomedical Sciences,** University of Guelph, Guelph, Canada; and the Clinics of General, Visceral, and Vascular Surgery,{ddagger} and the Departments of Physiological Chemistry§ and Pathology, Martin Luther University, Halle/Saale, Germany

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. Suppression of LGR7 expression by LGR7-siRNA abolished the RLN2-mediated accelerated tumor cell motility. The increased elastinolytic activity correlated with enhanced production and secretion of the lysosomal proteinases cathepsin-D (cath-D) and cath-L forms hereby identified as new RLN2 target molecules in human neoplastic thyrocytes. We found the intracellular distribution of procath-L specifically altered in RLN2 transfectants, providing first evidence for selective actions of relaxin on the powerful elastinolytic cath-L production, storage, and secretion in thyroid carcinoma cells. Thus, relaxin enhances the oncogenic potential and acts as novel endocrine modulator of invasiveness in human thyroid carcinoma cells.




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