LGR5 is associated with tumor aggressiveness in papillary thyroid cancer.
LGR5 is associated with tumor aggressiveness in papillary thyroid cancer.
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LGR5与乳头状甲状腺癌的肿瘤侵袭性有关。
DOI：
10.18632/oncotarget.5330
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发表时间：
2015-10-27
期刊：
影响因子：
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通讯作者：
Henderson BB
中科院分区：
文献类型：
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作者：
Michelotti G;Jiang X;Sosa JA;Diehl AM;Henderson BB
富含亮氨酸重复序列的G蛋白偶联受体5（LGR 5）是一种癌症干细胞标志物，也是Wnt/β-连环蛋白信号传导的下游靶点。在人甲状腺乳头状癌（PTC）中，Wnt/β-catenin的过度活化与肿瘤的侵袭性相关。使用已建立的人类细胞系（TPC-1、KTC-1、Nthy-ori-3-1），我们报告了LGR 5和R-spondin（RSPO 1 -3）在PTC中的过表达，并通过药理学和遗传干预来操纵LGR 5和Wnt/β-catenin信号传导。我们使用发现队列（n = 26例患者）和验证队列（n = 157例患者）检测LGR 5肿瘤表达与PTC侵袭性标志物的相关性。最后，我们探讨了LGR 5和BRAFV 600 E突变之间的关联（n = 33例患者）。我们的研究结果表明，LGR 5及其配体RSPO在人PTC中过表达，由此Wnt/β-连环蛋白信号调节LGR 5表达并促进细胞迁移。在两个单独的患者队列中，LGR 5和RSPO 2与肿瘤侵袭性标志物相关，包括：淋巴结转移、血管浸润、肿瘤大小增加、侵袭性组织学、晚期AJCC TNM分期、显微镜下甲状腺外延伸、包膜浸润和肉眼可见浸润。作为生物标志物，LGR 5阳性预测淋巴结转移的灵敏度为95.5%（95% CI 88.8%-98.7%），特异性为61%（95% CI：48.4%-72.4%），淋巴结转移性疾病的阴性预测值（NPV）为91.3%（95% CI 79.2%-97.5%）。在人PTC中，LGR 5也与BRAFV 600 E突变密切相关（p = 0.005）。我们的结论是LGR 5的过度表达与人PTC中肿瘤侵袭性的标志物有关。LGR 5可能作为PTC患者风险分层和局部区域转移的未来潜在生物标志物。
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.