Papillary thyroid cancer (PTC) is one of the most common endocrine
malignancies associated with significant morbidity and mortality. Although
multiple studies have contributed to a better understanding of the genetic
alterations underlying this frequently arising disease, the downstream molecular
effectors that impact PTC pathogenesis remain to be further defined. Here, we
report that the regulator of cell fate specification, PROX1, becomes inactivated
in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression
studies in clinical specimens revealed that aberrantly activated NOTCH signaling
promoted PROX1 downregulation and that cytoplasmic mislocalization significantly
altered PROX1 protein stability. Importantly, restoration of PROX1 activity in
thyroid carcinoma cells revealed that PROX1 not only enhanced
Wnt/β-catenin signaling, but also regulated several genes known to be
associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and
FABP4. Furthermore, PROX1 re-expression suppressed the malignant phenotypes of
thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion,
anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies
demonstrated that restoration of PROX1 severely impeded tumor formation and
suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells.
Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation
significantly promotes the malignant behavior of thyroid carcinoma, and suggest
that PROX1 reactivation may represent a potential therapeutic strategy to
attenuate disease progression