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Sprouty2 反馈失调在 BRAF V600E 突变阳性甲状腺乳头状癌中的临床和治疗意义。

Clinical and therapeutic implications of Sprouty2 feedback dysregulation in BRAF V600E-mutation-positive papillary thyroid cancer.

机构信息

Department of Surgery, Division of Endocrine Surgery, New York University School of Medicine, New York, NY.

出版信息

Surgery. 2013 Dec;154(6):1239-44; discussion 1244-5. doi: 10.1016/j.surg.2013.06.024. Epub 2013 Oct 2.

DOI:10.1016/j.surg.2013.06.024
PMID:24094449
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4100696/
Abstract

BACKGROUND

The BRAF V600E (BRAF+) mutation activates the mitogen-activated protein kinase (MAPK/ERK) pathway and may confer an aggressive phenotype in papillary thyroid cancer (PTC). Clinically, the behavior of BRAF+ PTC, however, varies from an indolent to an aggressive course. SPRY2 is a negative feedback regulator of the MAPK/ERK pathway. We hypothesize that the level of SPRY2 expression contributes to MAPK/ERK pathway output and accounts for BRAF+ and clinical heterogeneity.

METHODS

A tissue microarray with BRAF-positive PTCs (BRAF+ PTCs) was constructed and analyzed for SPRY2 expression and MAPK/ERK output. Data were studied in the context of clinicopathologic factors to develop a risk stratification system predictive of tumor biology. SPRY2 function was studied by silencing SPRY2 in BRAF+ PTC cells. These cells were treated with MAPK/ERK pathway inhibitors and assessed for growth effects.

RESULTS

BRAF+ PTCs with an intact MAPK/ERK feedback pathway do not exhibit lymph node metastases. BRAF+ PTCs with dysregulated feedback pathways have nodal metastasis. When SPRY2 is silenced, the BRAF+ PTC cells are significantly more sensitive to MAPK/ERK inhibition.

CONCLUSION

PTC behavior likely is dependent on both the driver of the MAPK/ERK pathway and its regulatory feedback. When the feedback pathway is intact, the tumor phenotype seems to be less aggressive. This observation has direct and important clinical implications and may alter our treatment strategies.

摘要

背景

BRAF V600E（BRAF+）突变激活丝裂原活化蛋白激酶（MAPK/ERK）通路，并可能在甲状腺乳头状癌（PTC）中赋予侵袭性表型。然而，临床上 BRAF+ PTC 的行为从惰性到侵袭性不等。SPRY2 是 MAPK/ERK 通路的负反馈调节剂。我们假设 SPRY2 表达水平有助于 MAPK/ERK 通路的输出，并解释了 BRAF+和临床异质性。

方法

构建了含有 BRAF 阳性 PTC（BRAF+ PTC）的组织微阵列，并分析了 SPRY2 表达和 MAPK/ERK 输出。根据临床病理因素研究数据，以开发预测肿瘤生物学的风险分层系统。通过沉默 BRAF+ PTC 细胞中的 SPRY2 研究 SPRY2 功能。用 MAPK/ERK 通路抑制剂处理这些细胞，并评估其生长效应。

结果

具有完整 MAPK/ERK 反馈通路的 BRAF+ PTC 无淋巴结转移。具有失调反馈通路的 BRAF+ PTC 有淋巴结转移。当沉默 SPRY2 时，BRAF+ PTC 细胞对 MAPK/ERK 抑制更为敏感。

结论

PTC 的行为可能依赖于 MAPK/ERK 通路的驱动因素及其调节反馈。当反馈通路完整时，肿瘤表型似乎不那么具有侵袭性。这一观察结果具有直接而重要的临床意义，并可能改变我们的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eda4/4100696/6a7ce9cf4697/nihms558066f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eda4/4100696/b81e959cfb8f/nihms558066f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eda4/4100696/faacfaca2047/nihms558066f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eda4/4100696/59cb10dcbab9/nihms558066f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eda4/4100696/6a7ce9cf4697/nihms558066f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eda4/4100696/b81e959cfb8f/nihms558066f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eda4/4100696/faacfaca2047/nihms558066f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eda4/4100696/59cb10dcbab9/nihms558066f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/eda4/4100696/6a7ce9cf4697/nihms558066f4.jpg

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