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LGR5 is associated with tumor aggressiveness in papillary thyroid cancer.

Publication ,  Journal Article
Michelotti, G; Jiang, X; Sosa, JA; Diehl, AM; Henderson, BB
Published in: Oncotarget
October 27, 2015

PURPOSE: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/β-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/β-catenin has been associated with tumor aggressiveness. PATIENTS AND METHODS: Using established human cell lines (TPC-1, KTC-1, Nthy-ori-3-1), we report LGR5 and R-spondin (RSPO1-3) overexpression in PTC and manipulate LGR5 and Wnt/β-catenin signaling via both pharmacologic and genetic interventions. We test the association of LGR5 tumor expression with markers of PTC aggressiveness using a Discovery Cohort (n = 26 patients) and a Validation Cohort (n = 157 patients). Lastly, we explore the association between LGR5 and the BRAFV600E mutation (n = 33 patients). RESULTS: Our results reveal that LGR5 and its ligand, RSPO, are overexpressed in human PTC, whereby Wnt/β-catenin signaling regulates LGR5 expression and promotes cellular migration. In two separate cohorts of patients, LGR5 and RSPO2 were associated with markers of tumor aggressiveness including: lymph node metastases, vascular invasion, increased tumor size, aggressive histology, advanced AJCC TNM stage, microscopic extra thyroidal extension, capsular invasion, and macroscopic invasion. As a biomarker, LGR5 positivity predicts lymph node metastasis with 95.5% sensitivity (95% CI 88.8%-98.7%) and 61% specificity (95% CI: 48.4%-72.4%) and has a negative predictive value (NPV) of 91.3% (95% CI 79.2%-97.5%) for lymph node metastatic disease. In human PTC, LGR5 is also strongly associated with the BRAFV600E mutation (p = 0.005). CONCLUSION: We conclude that overexpression of LGR5 is associated with markers of tumor aggressiveness in human PTC. LGR5 may serve as a future potential biomarker for patient risk stratification and loco regional metastases in PTC.

Duke Scholars

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

October 27, 2015

Volume

6

Issue

33

Start / End Page

34549 / 34560

Location

United States

Related Subject Headings

  • beta Catenin
  • Wnt Signaling Pathway
  • Thyroid Neoplasms
  • Thyroid Cancer, Papillary
  • Thrombospondins
  • Sensitivity and Specificity
  • Receptors, G-Protein-Coupled
  • Real-Time Polymerase Chain Reaction
  • Proto-Oncogene Proteins B-raf
  • Mutation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Michelotti, G., Jiang, X., Sosa, J. A., Diehl, A. M., & Henderson, B. B. (2015). LGR5 is associated with tumor aggressiveness in papillary thyroid cancer. Oncotarget, 6(33), 34549–34560. https://doi.org/10.18632/oncotarget.5330
Michelotti, Gregory, Xiaoyin Jiang, Julie Ann Sosa, Anna Mae Diehl, and Brittany Bohinc Henderson. “LGR5 is associated with tumor aggressiveness in papillary thyroid cancer.Oncotarget 6, no. 33 (October 27, 2015): 34549–60. https://doi.org/10.18632/oncotarget.5330.
Michelotti G, Jiang X, Sosa JA, Diehl AM, Henderson BB. LGR5 is associated with tumor aggressiveness in papillary thyroid cancer. Oncotarget. 2015 Oct 27;6(33):34549–60.
Michelotti, Gregory, et al. “LGR5 is associated with tumor aggressiveness in papillary thyroid cancer.Oncotarget, vol. 6, no. 33, Oct. 2015, pp. 34549–60. Pubmed, doi:10.18632/oncotarget.5330.
Michelotti G, Jiang X, Sosa JA, Diehl AM, Henderson BB. LGR5 is associated with tumor aggressiveness in papillary thyroid cancer. Oncotarget. 2015 Oct 27;6(33):34549–34560.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

October 27, 2015

Volume

6

Issue

33

Start / End Page

34549 / 34560

Location

United States

Related Subject Headings

  • beta Catenin
  • Wnt Signaling Pathway
  • Thyroid Neoplasms
  • Thyroid Cancer, Papillary
  • Thrombospondins
  • Sensitivity and Specificity
  • Receptors, G-Protein-Coupled
  • Real-Time Polymerase Chain Reaction
  • Proto-Oncogene Proteins B-raf
  • Mutation