Dataset Information

Hedgehog signaling in human medullary thyroid carcinoma: a novel signaling pathway.

ABSTRACT: Locally or widely metastatic medullary thyroid carcinoma (MTC) is difficult to treat, and therapeutic options are limited. Recently, kinase inhibitors have shown partial efficacy in this cancer, but there is a continued need for the development of novel therapeutics. Within this context, the Hedgehog (Hh) pathway has been implicated in several types of human tumors, and early clinical trials with Hh antagonists have validated Hh as a novel therapeutic target. For the first time, we evaluated Hh pathway activity in MTC, and examined the effect of Hh pathway perturbation in highly characterized MTC cell lines.We examined immunohistochemical expression of the Hh signaling mediators Sonic Hedgehog (Shh) and Glioblastoma (Gli)2 in paraffin-embedded normal versus histologically characterized human MTC tissue. We examined pharmacologic disruption of Hh signaling in vitro using two established MTC cell lines (TT and MZ-CRC-1). Hh signaling was either pharmacologically activated (SAG) or inhibited (GDC-0449) in MTC cell lines; Hh activity was assessed by quantitative real-time polymerase chain reaction, Western blot analysis, and quantification of cellular growth and apoptotic activity.Our data showed increased expression of Hh signaling factors in human MTC compared to normal tissue. In vitro, activation of the Hh pathway resulted in increased expression of key Hh signaling components Smoothened (Smo) and Gli2. Conversely, inhibition of the Hh pathway decreased expression of these genes, leading to significantly reduced cellular growth and increased apoptosis.Hedgehog signaling components are markedly upregulated in MTC. Hh pathway inhibitors have potential as novel therapeutic options in patients with metastatic and/or surgically unresectable MTC.

SUBMITTER: Bohinc B

PROVIDER: S-EPMC3770247 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Hedgehog signaling in human medullary thyroid carcinoma: a novel signaling pathway.

Bohinc Brittany B Michelotti Gregory G Diehl Anna Mae AM

Thyroid : official journal of the American Thyroid Association 20130901 9

<h4>Background</h4>Locally or widely metastatic medullary thyroid carcinoma (MTC) is difficult to treat, and therapeutic options are limited. Recently, kinase inhibitors have shown partial efficacy in this cancer, but there is a continued need for the development of novel therapeutics. Within this context, the Hedgehog (Hh) pathway has been implicated in several types of human tumors, and early clinical trials with Hh antagonists have validated Hh as a novel therapeutic target. For the first tim ...[more]

PMID: 23410206

Similar Datasets

Project description:Hedgehog (Hh) signaling plays an important role in embryonic development and in the regulation of a variety of cellular functions. Aberrant activation of Hh signaling has been implicated in several human cancers including hepatocellular carcinoma (HCC). In this study we examined the pathobiological functions and molecular mechanisms of the Hh signaling pathway in HCC cells. Treatment of cultured human HCC cells (Huh7, Hep3B, and HepG2) with the Hh signaling ligand (recombinant Shh) or agonist, SAG and purmorphamine, prevented the induction of autophagy. In contrast, GANT61 (a small molecule inhibitor of Gli1 and Gli2) induced autophagy, as determined by immunoblotting for microtubule-associated protein light chain 3 (LC3) and p62, GFP-LC3 puncta, monodansylcadaverine (MDC) staining, and transmission electron microscopy. Hh inhibition-induced autophagy was associated with up-regulation of Bnip3, as determined by immunoblotting and real-time polymerase chain reaction (PCR) assay. Knockdown of Bnip3 by RNAi impaired GANT61-induced autophagy. Additionally, Hh inhibition-induced autophagy was associated with Bnip3-mediated displacement of Bcl-2 from Beclin-1, as determined by immunoblotting and immunoprecipitation assays. Furthermore, inhibition of Hh signaling increased HCC cell apoptosis and decreased cell viability, as determined by caspase and WST-1 assays. Pharmacological or genetic inhibition of autophagy by 3-methyladenine (3-MA) or Beclin-1 small interfering RNA (siRNA) partially suppressed GANT61-induced cell apoptosis and cytotoxicity. In a tumor xenograft model using SCID mice inoculated with Huh7 cells, administration of GANT61 inhibited tumor formation and decreased tumor volume; this effect was partially blocked by the autophagy inhibitor, 3-MA.These findings provide novel evidence that Hh inhibition induces autophagy through up-regulation of Bnip3 and that this mechanism contributes to apoptosis. Therefore, the status of autophagy is a key factor that determines the therapeutic response to Hh-targeted therapies.

Dataset Information

Hedgehog signaling in human medullary thyroid carcinoma: a novel signaling pathway.

Publications

Hedgehog signaling in human medullary thyroid carcinoma: a novel signaling pathway.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets