Department of Experimental Medicine, University of Rome, Rome, Italy.
Clin Endocrinol (Oxf). 2012 Nov;77(5):780-6. doi: 10.1111/j.1365-2265.2012.04465.x.
It has been suggested that patients with papillary thyroid cancer (PTC) harbouring the BRAF(V600E) mutation have a worse prognosis. We showed in PTC that high levels of urokinase plasminogen activator (uPA) and its cognate receptor (uPAR) inversely correlate with disease-free interval (DFI).
To investigate the effects of BRAF(V600E) on the expression of uPA and uPAR and to evaluate the prognostic relevance of BRAF(V600E) alone or in combination with uPA and uPAR. DESIGN/SETTING/PATIENTS/INTERVENTION: The case study included 91 patients with PTC. All patients underwent thyroidectomy and radioiodine therapy. Follow-up was available for 75 patients.
The BRAF(V600E) mutation was analysed by sequencing and mutant allele-specific PCR amplification; uPA and uPAR expression by quantitative RT-PCR.
BRAF(V600E) was found in 44 of the 91 patients and associated with older age, but not with high-risk clinicopathological features. Urokinase PA and uPAR mRNA levels were higher in tumour tissues by 9·51 ± 1·30 and 4·64 ± 0·44 fold, respectively, compared to normal matched tissues, being significantly higher in BRAF(V600E) -positive patients. In vitro induction of BRAF(V600E) in PCCL3 cells caused a significant increase in both uPA and uPAR mRNAs. Higher levels of uPA and uPAR correlated with lymph node metastases, TNM stage and disease recurrences. Kaplan-Meier and multivariate analyses demonstrated that uPA and uPAR were associated with shorter DFI, while the BRAF(V600E) was not.
In PTC, BRAF(V600E) induces uPA and uPAR expression. The latter, but not BRAF(V600E) , associates with advanced stages and shorter DFI. If confirmed in larger case studies, they may represent reliable prognostic markers for more accurate risk stratification and postoperative decision-making in patients with PTC.
已有研究表明，携带 BRAF(V600E) 突变的甲状腺乳头状癌（PTC）患者预后较差。我们在 PTC 中发现，尿激酶纤溶酶原激活物（uPA）及其同源受体（uPAR）的高水平与无病间隔（DFI）呈负相关。
研究 BRAF(V600E) 对 uPA 和 uPAR 表达的影响，并评估 BRAF(V600E) 单独或与 uPA 和 uPAR 联合的预后相关性。
设计/地点/患者/干预：本病例研究纳入 91 例 PTC 患者。所有患者均接受甲状腺切除术和放射性碘治疗。75 例患者可获得随访。
通过测序和突变等位基因特异性 PCR 扩增分析 BRAF(V600E) 突变；通过定量 RT-PCR 分析 uPA 和 uPAR 表达。
91 例患者中有 44 例发现 BRAF(V600E)，与年龄较大有关，但与高危临床病理特征无关。与正常配对组织相比，肿瘤组织中 uPA 和 uPAR mRNA 水平分别升高 9.51±1.30 倍和 4.64±0.44 倍，且在 BRAF(V600E)阳性患者中更高。在 PCCL3 细胞中诱导 BRAF(V600E)可显著增加 uPA 和 uPAR mRNA 的表达。uPA 和 uPAR 水平较高与淋巴结转移、TNM 分期和疾病复发相关。Kaplan-Meier 和多因素分析表明，uPA 和 uPAR 与 DFI 缩短相关，而 BRAF(V600E) 则无此相关性。
在 PTC 中，BRAF(V600E) 诱导 uPA 和 uPAR 表达。后者而不是 BRAF(V600E)与晚期阶段和较短的 DFI 相关。如果在更大的病例研究中得到证实，它们可能成为可靠的预后标志物，用于更准确地对 PTC 患者进行风险分层和术后决策。
