Department of Oral and Maxillofacial Plastic Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str, 40 06097, Halle/Saale, Germany.
Present address: Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
BMC Cancer. 2019 Feb 15;19(1):155. doi: 10.1186/s12885-019-5327-8.
The human leucine-rich, repeat-containing G protein-coupled receptor 5 (LGR5) is a stem cell marker in numerous adult tissues and is overexpressed in a large number of human carcinoma including colon cancer, breast cancer and oral squamous cell carcinomas (OSCC). The role of the full length transcript (LGR5FL) in progression and prognosis of several cancers was reported. However, the biological function of three splice variants of LGR5 (LGR5Δ5, LGR5Δ8 and LGR5Δ5-8) has yet to be thoroughly investigated.
Seventy-eight frozen tumor samples from adult OSCC patients were studied using quantitative real-time TaqMan™ PCR analysis. The mRNA levels of full length LGR5, the splice variant of LGR5 lacking exon 5 (LGR5Δ5), the splice variant of LGR5 lacking exon 8 (LGR5Δ8) and the mRNA level of all known transcript variants together (LGR5all) were quantified and correlated to overall and disease-specific survival of OSCC patients, clinical parameters and the mRNA level of different tumor-associated markers.
An elevated level of tumoral LGR5Δ5 mRNA, but not LGR5FL, LGR5Δ8 or LGR5all mRNA was significantly associated with a poor prognosis for the overall and disease-specific survival of OSCC patients (hazard ratio (HR) = 2.0; p = 0.02; 95% CI: 1.1-3.7; HR = 3.2; p = 0.01; 95% CI: 1.3-8.0; multivariable Cox regression), respectively. Additionally, a higher tumoral level of LGR5Δ5 mRNA in primary tumors was associated with the occurrence of regional lymph node metastases in OSCC patients (odds ratio (OR) = 3.1; p = 0.022; 95% CI: 1.2-7.9; binary logistic regression). Furthermore, the mRNA levels of all investigated LGR5 transcript variants were significantly correlated with the mRNA expression of Wnt-target genes and markers of epithelial-to-mesenchymal transition (EMT).
The mRNA level of the LGR5 splice variant LGR5Δ5 is an independent negative prognostic marker for overall and disease-specific survival and metastasis in OSCC patients. Additionally, we suggest, all LGR5 transcript variants are involved in the EMT process mainly through activating the Wnt-signalling pathway.
人类富含亮氨酸重复序列的 G 蛋白偶联受体 5（LGR5）是许多成人组织中的干细胞标志物，在包括结肠癌、乳腺癌和口腔鳞状细胞癌（OSCC）在内的大量人类癌中过表达。全长转录本（LGR5FL）在几种癌症的进展和预后中的作用已被报道。然而，LGR5 的三种剪接变体（LGR5Δ5、LGR5Δ8 和 LGR5Δ5-8）的生物学功能尚未得到彻底研究。
使用定量实时 TaqMan™ PCR 分析研究了 78 例成年 OSCC 患者的 78 例冷冻肿瘤样本。全长 LGR5、缺失外显子 5 的 LGR5 剪接变体（LGR5Δ5）、缺失外显子 8 的 LGR5 剪接变体（LGR5Δ8）和所有已知转录变体的 mRNA 水平（LGR5all）进行定量，并与 OSCC 患者的总体和疾病特异性生存率、临床参数以及不同肿瘤相关标志物的 mRNA 水平相关联。
肿瘤 LGR5Δ5 mRNA 水平升高，但 LGR5FL、LGR5Δ8 或 LGR5all mRNA 水平升高与 OSCC 患者的总体和疾病特异性生存率不良相关（风险比（HR）=2.0；p=0.02；95%CI：1.1-3.7；HR=3.2；p=0.01；95%CI：1.3-8.0；多变量 Cox 回归）。此外，LGR5Δ5 mRNA 在原发性肿瘤中的高肿瘤水平与 OSCC 患者的区域淋巴结转移发生相关（比值比（OR）=3.1；p=0.022；95%CI：1.2-7.9；二项逻辑回归）。此外，所有研究的 LGR5 转录变体的 mRNA 水平与 Wnt 靶基因和上皮-间充质转化（EMT）标志物的 mRNA 表达显著相关。
LGR5 剪接变体 LGR5Δ5 的 mRNA 水平是 OSCC 患者总体和疾病特异性生存率以及转移的独立负预后标志物。此外，我们认为所有 LGR5 转录变体均通过激活 Wnt 信号通路参与 EMT 过程。
