Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Transl Oncol. 2009 Dec;2(4):236-41. doi: 10.1593/tlo.09151.
Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy and RET/PTC rearrangements represent key genetic events frequently associated to this cancer, enhancing proliferation and dedifferentiation by activation of the RET/PTC-RAS-BRAF-mitogen-activated protein kinase (MAPK) pathway. Recently, let-7 microRNA was found to reduce RAS levels in lung cancer, acting as a tumor suppressor gene. Here, we report that RET/PTC3 oncogenic activation in PCCL3 rat thyroid cells markedly reduces let-7f expression. Moreover, stable transfection of let-7 microRNA in TPC-1 cells, which harbor RET/PTC1 rearrangement, inhibits MAPK activation. As a result, let-7f was capable of reducing TPC-1 cell growth, and this might be explained, at least in part, by decreased messenger RNA (mRNA) expression of cell cycle stimulators such as MYC and CCND1 (cyclin D1) and increased P21 cell cycle inhibitor mRNA. In addition, let-7 enhanced transcriptional expression of molecular markers of thyroid differentiation such as TITF1 and TG. Thus, reduced expression of let-7f might be an essential molecular event in RET/PTC malignant transformation. Moreover, let-7f effects on thyroid growth and differentiation might attenuate neoplastic process of RET/PTC papillary thyroid oncogenesis through impairment of MAPK signaling pathway activation. This is the first functional demonstration of an association of let-7 with thyroid cancer cell growth and differentiation.
甲状腺乳头状癌（PTC）是最常见的内分泌恶性肿瘤，RET/PTC 重排是与这种癌症密切相关的关键遗传事件，通过激活 RET/PTC-RAS-BRAF-丝裂原活化蛋白激酶（MAPK）通路，促进增殖和去分化。最近，发现 let-7 微 RNA 可降低肺癌中的 RAS 水平，作为一种肿瘤抑制基因发挥作用。在这里，我们报告 RET/PTC3 癌基因激活可显著降低 PCCL3 大鼠甲状腺细胞中的 let-7f 表达。此外，RET/PTC1 重排的 TPC-1 细胞中稳定转染 let-7 微 RNA 可抑制 MAPK 激活。结果，let-7f 能够降低 TPC-1 细胞的生长，这至少部分可以解释为细胞周期刺激物如 MYC 和 CCND1（细胞周期蛋白 D1）的信使 RNA（mRNA）表达减少和 P21 细胞周期抑制剂 mRNA 增加。此外，let-7 增强了甲状腺分化的分子标志物如 TITF1 和 TG 的转录表达。因此，let-7f 的表达降低可能是 RET/PTC 恶性转化的一个重要分子事件。此外，let-7f 对甲状腺生长和分化的影响可能通过抑制 MAPK 信号通路的激活来减弱 RET/PTC 甲状腺癌发生的肿瘤过程。这是首次证明 let-7 与甲状腺癌细胞生长和分化之间存在关联。
