Divisions of Endocrinology, Diabetes, and Metabolism, The Ohio State University College of Medicine and Arthur G. James Comprehensive Cancer Center, Columbus, OH, USA.
Oncogene. 2011 Oct 20;30(42):4307-15. doi: 10.1038/onc.2011.136. Epub 2011 May 2.
Akt activation is common in progressive thyroid cancer. In breast cancer, Akt1 induces primary cancer growth, but is reported to inhibit metastasis in vivo in several model systems. In contrast, clinical and in vitro studies suggest a metastasis-promoting role for Akt1 in thyroid cancer. The goal of this study was to determine the functional role of Akt1 in thyroid cancer growth and metastatic progression in vivo using thyroid hormone receptor (TR) β(PV/PV) knock-in (PV) mice, which develop metastatic thyroid cancer. We crossed Akt1(-/-) and PV mice and compared tumor development, local progression, metastasis and histology in TRβ(PV/PV)/Akt1(+/+) (PVPV-Akt1WT) and TRβ(PV/PV)/Akt1(-/-) (PVPV-Akt1KO) mice. Mice were killed at 3, 6, 9, 12 and 15 months; necropsy was performed and serum thyroid stimulating hormone (TSH) was measured. Thyroid hyperplasia occurred in both groups beginning at 3 months; the thyroid size was greater in the PVPV-Akt1WT mice (P<0.001). In comparison with PVPV-Akt1WT mice, thyroid cancer development was delayed in the PVPV-Akt1KO mice (P=0.003) and the degree of tumor invasiveness was reduced. The PVPV-Akt1WT mice displayed pulmonary metastases at 12 and 15 months of age, by contrast PVPV-Akt1KO mice did not develop distant metastases at 15 months of age. Despite continued expression of Akt2 or Akt3, pAkt levels were decreased and there was evidence of reduced Akt effect on p27 in the PVPV-Akt1KO thyroids. TSH levels were similarly elevated in PV mice regardless of Akt1 expression. In conclusion, thyroid cancer development and progression in TR β(PV/PV) mice are Akt1-dependent, consistent with a tumor progression-promoting role in this murine thyroid cancer model.
Akt 的激活在进展期甲状腺癌中很常见。在乳腺癌中，Akt1 诱导原发性癌症生长，但在几种模型系统中被报道抑制体内转移。相比之下，临床和体外研究表明 Akt1 在甲状腺癌中具有促进转移的作用。本研究的目的是使用甲状腺激素受体 (TR) β(PV/PV) 敲入 (PV) 小鼠确定 Akt1 在甲状腺癌生长和体内转移进展中的功能作用，PV 小鼠会发展出转移性甲状腺癌。我们将 Akt1(-/-)和 PV 小鼠进行杂交，并比较 TRβ(PV/PV)/Akt1(+/+) (PVPV-Akt1WT) 和 TRβ(PV/PV)/Akt1(-/-) (PVPV-Akt1KO) 小鼠的肿瘤发展、局部进展、转移和组织学。小鼠在 3、6、9、12 和 15 个月时被处死；进行尸检并测量血清促甲状腺激素 (TSH)。两组均在 3 个月时开始出现甲状腺增生；PVPV-Akt1WT 小鼠的甲状腺大小更大 (P<0.001)。与 PVPV-Akt1WT 小鼠相比，PVPV-Akt1KO 小鼠的甲状腺癌发展延迟 (P=0.003)，肿瘤侵袭程度降低。PVPV-Akt1WT 小鼠在 12 和 15 个月时出现肺转移，而 PVPV-Akt1KO 小鼠在 15 个月时未发生远处转移。尽管 Akt2 或 Akt3 的表达持续存在，但 pAkt 水平降低，并且在 PVPV-Akt1KO 甲状腺中观察到 Akt 对 p27 的作用降低。无论 Akt1 的表达如何，PV 小鼠的 TSH 水平都相似地升高。总之，TRβ(PV/PV) 小鼠中甲状腺癌的发展和进展依赖于 Akt1，与该小鼠甲状腺癌模型中促进肿瘤进展的作用一致。
