Abstract
Background: Thyroid cancer is the most common endocrine malignancy, and many patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) fail to respond to conventional therapies, resulting in morbidity and mortality. Additional therapeutic targets and treatment options are needed for these patients. We recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in ATC and confers an aggressive phenotype when overexpressed in DTC cells.Methods: Microarray analysis was used to identify downstream targets of PPARγ in ATC cells. Western blot analysis and immunohistochemistry (IHC) were used to assess thioredoxin interacting protein (TXNIP) expression in thyroid cancer cell lines and primary tumor specimens. Retroviral transduction was used to generate ATC cell lines that overexpress TXNIP, and assays that assess glucose uptake, viable cell proliferation, and invasion were used to characterize the in vitro properties of these cells. An orthotopic thyroid cancer mouse model was used to assess the effect of TXNIP overexpression in ATC cell lines in vivo.Results: Using microarray analysis, we show that TXNIP is highly upregulated when PPARγ is depleted from ATC cells. Using Western blot analysis and IHC, we show that DTC and ATC cells exhibit differential TXNIP expression patterns. DTC cell lines and patient tumors have high TXNIP expression in contrast to low or absent expression in ATC cell lines and tumors. Overexpression of TXNIP decreases the growth of HTh74 cells compared to vector controls and inhibits glucose uptake in the ATC cell lines HTh74 and T238. Importantly, TXNIP overexpression in T238 cells results in attenuated tumor growth and decreased metastasis in an orthotopic thyroid cancer mouse model.Conclusions: Our findings indicate that TXNIP functions as a tumor suppressor in thyroid cells, and its downregulation is likely important in the transition from differentiated to advanced thyroid cancer. These studies underscore the potential of TXNIP as a novel therapeutic target and prognostic indicator in advanced thyroid cancer.
| Original language | English |
|---|---|
| Article number | 62 |
| Journal | Molecular Cancer |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2014 Mar 19 |
Bibliographical note
Funding Information:We acknowledge the generous support of our funding sources: American Thyroid Association Research Grant Award (JAM), National Institutes of Health (NIH)/National Cancer Institute (NCI) Ruth L. Kirschstein National Research Service Award for Individual Postdoctoral Fellows F32 CA174374 (JAM), NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Endocrinology, Diabetes, & Metabolism Training Grant Award T32 DK007446-31 (JAM), Endocrine Fellows Foundation Endocrine Research Grant (JAM), NIH/NCI Research Grant 1R01 CA175994 (BRH, WMW), the Mary Rossick Kern and Jerome H Kern Endowment for Endocrine Neoplasms Research (BRH), and the University of Colorado Cancer Center Gene Expression and Small Animal Imaging Cores supported by NCI Cancer Center Support Grant P30 CA46934. The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank Parth Patwari for the generous gift of the plasmid encoding human TXNIP in pcDNA3.1. We thank Isabel R. Schlaepfer and Rebecca E. Schweppe for technical advice and instruction as well as scientific discussion. We are grateful to Uma Pugazhenthi in the University of Colorado PCR core for assistance with GFP qRT-PCR and Heather Selby for assistance with the microarray analysis.
Keywords
- Orthotopic model
- PPARγ
- TXNIP
- Thioredoxin interacting protein
- Thyroid cancer
- Tumor suppressor
ASJC Scopus subject areas
- Molecular Medicine
- Oncology
- Cancer Research
