期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 4, 页码 1615-1620出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1015557108
关键词
Ras; G protein; pax8
资金
- National Institutes of Health (NIH) [CA50706, CA72597, DK17050, F32CA136178, P50-CA92629]
- Margot Rosenberg Pulitzer Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases
- Small Animal Imaging Research Program [R24 CA83084]
- NIH Center [P30 CA08748]
- Cancer Research UK [13083] Funding Source: researchfish
Mutations of BRAF are found in similar to 45% of papillary thyroid cancers and are enriched in tumors with more aggressive properties. We developed mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf(V600E)/TPO-Cre) to explore the role of endogenous expression of this oncoprotein on tumor initiation and progression. In contrast to other Braf-induced mouse models of tumorigenesis (i.e., melanomas and lung), in which knock-in of Braf(V600E) induces mostly benign lesions, Braf-expressing thyrocytes become transformed and progress to invasive carcinomas with a very short latency, a process that is dampened by treatment with an allosteric MEK inhibitor. These mice also become profoundly hypothyroid due to deregulation of genes involved in thyroid hormone biosynthesis and consequently have high TSH levels. To determine whether TSH signaling cooperates with oncogenic Braf in this process, we first crossed LSL-Braf(V600E)/TPO-Cre with TshR knockout mice. Although oncogenic Braf was appropriately activated in thyroid follicular cells of these mice, they had a lower mitotic index and were not transformed. Thyroid-specific deletion of the Gs alpha gene in LSL-Braf(V600E)/TPO-Cre/Gnas-E1(fl/fl) mice also resulted in an attenuated cancer phenotype, indicating that the cooperation of TshR with oncogenic Braf is mediated in part by cAMP signaling. Once tumors were established in mice with wild-type TshR, suppression of TSH did not revert the phenotype. These data demonstrate the key role of TSH signaling in Braf-induced papillary thyroid cancer initiation and provide experimental support for recent observations in humans pointing to a strong association between TSH levels and thyroid cancer incidence.
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