Follicular thyroid cancer (
FTC) is known to metastasize to distant sites via hematogenous spread; however, the underlying pathways that contribute to
metastasis remain unknown. Recent creation of a knockin mutant mouse that expresses a mutant
thyroid hormone receptor-beta (TRbeta(PV/PV) mouse) that spontaneously develops
thyroid cancer with
metastasis similar to humans has provided new opportunities to study contributors to
FTC metastasis. This study evaluates the role of
gelsolin, an actin-regulatory
protein, in modulating the metastatic potential of
FTC.
Gelsolin was previously found by
cDNA microarray analysis to be down-regulated in TRbeta(PV/PV) mice as compared with wild-type mice. This study found an age-dependent reduction of
gelsolin protein abundance in TRbeta(PV/PV) mice as
tumorigenesis progressed. Knockdown of
gelsolin by
small interfering RNA resulted in increased
tumor cell motility and increased
gelsolin expression by
histone deacetylase inhibitor (
trichostatin A) led to decreased cell motility. Additional biochemical analyses demonstrated that
gelsolin physically interacted with TRbeta1 or PV in vivo and in vitro. The interaction regions were mapped to the C terminus of
gelsolin and the
DNA binding domain of TR. The physical interaction of
gelsolin with PV reduced its binding to actin, leading to disarrayed cytoskeletal architectures. These results suggest that PV-induced alteration of the actin/
gelsolin cytoskeleton contributes to increased cell motility. Thus, the present study uncovered a novel PV-mediated oncogenic pathway that could contribute to the local
tumor progression and metastatic potential of thyroid
carcinogenesis.