Research Papers:

LGR5 is associated with tumor aggressiveness in papillary thyroid cancer

Gregory Michelotti _, Xiaoyin Jiang, Julie Ann Sosa, Anna Mae Diehl and Brittany Bohinc Henderson

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Oncotarget. 2015; 6:34549-34560. https://doi.org/10.18632/oncotarget.5330

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Gregory Michelotti1, Xiaoyin Jiang2, Julie Ann Sosa3, Anna Mae Diehl1, Brittany Bohinc Henderson4

1Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina, USA

2Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA

3Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA

4Division of Endocrinology, Diabetes and Metabolism, Wake Forest University, Winston-Salem, North Carolina, USA

Correspondence to:

Brittany Bohinc Henderson, e-mail: [email protected]

Keywords: R-spondin, Wnt, β-catenin, metastasis, BRAFV600E

Received: May 07, 2015     Accepted: September 14, 2015     Published: September 25, 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.

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