Abstract
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. 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). 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). 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.
Highlights
The Wnt/β-catenin signaling pathway plays an important role in stem cell proliferation, tissue differentiation, and cellular polarity [1,2]
Our results reveal that Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) and its ligand, RSPO, are overexpressed in human papillary thyroid cancer (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 American Joint Committee on Cancer (AJCC) TNM stage, microscopic extra thyroidal extension, capsular invasion, and macroscopic invasion
Summary
The Wnt/β-catenin signaling pathway plays an important role in stem cell proliferation, tissue differentiation, and cellular polarity [1,2]. Dysregulation of Wnt/β-catenin signaling contributes to the development of human papillary thyroid cancer (PTC), potentiating cancer stem cell proliferation, disruption of thyroid microarchitecture, tumor dedifferentiation, extra capsular spread, and angioinvasion [3,4,5]. Theories on thyroid cancer biogenesis have migrated from the classical explanation (i.e “multi-hit” genetic mutations and environmental exposures) to the promotion of tumorgenesis by proliferation of cancer stem cells (CSCs) [6,7]. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is expressed on CSCs and is a known downstream target gene of the Wnt/β-catenin pathway [8,9,10,11,12]. A characteristic feature of all four RSPO members is their ability to activate LGR5-frizzled lipoprotein receptor-related protein 5 and 6 (LRP5/6) binding and enhance Wnt-mediated β-catenin activation. [15,16,17,18,19,20]
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