RAF-1 promotes survival of thyroid cancer cells harboring RET/PTC1 rearrangement independently of ERK activation
RAF-1 promotes survival of thyroid cancer cells harboring RET/PTC1 rearrangement independently of ERK activation
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DOI：
10.1016/j.mce.2015.08.006
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发表时间：
2015-11-05
影响因子：
4.1
通讯作者：
Preto, Ana
中科院分区：
文献类型：
--
作者：
Castro, Lisandra;Alves, Sara;Preto, Ana
甲状腺癌 (TC) 通常与 BRAF 或 RAS 致癌突变和 RET/PTC 重排以及异常的 RAF-MEK-ERK 和/或 PI3K 通路激活相关。 BRAF 是大多数 TC 细胞中 ERR 激活的基础，但在具有 RET/PTC1 重排的 TPC-1 细胞中则不然。在这里，我们发现，RAF-1（一种在 TC 中作用不明确的 RAF 家族成员）的缺失会减少 TPC-1 细胞的增殖并增加细胞凋亡，而在含有 BRAF（V600E）或 HRAS（G13R）突变的细胞中则不太显着，但不影响 ERR 激活。我们进一步证明，TPC-1 细胞中 ERK 的组成性激活不是由容易激活 ERR 通路的 50 种癌基因和抑癌基因突变引起的，也不是受到 BRAF、MEK1/2 或 PI3K 抑制的影响。我们的数据表明，RAF-1 对于 TPC-1 细胞的存活很重要，独立于经典的 MEK1/2-ERK 激活，为 RET/PTC 信号传导和甲状腺癌的治疗提供了新的视角。 (C) 2015 Elsevier Ireland Ltd. 保留所有权利。
Thyroid cancer (TC) is frequently associated with BRAF or RAS oncogenic mutations and RET/PTC rear-rangements, with aberrant RAF-MEK-ERK and/or PI3K pathway activation. BRAF underlies ERR activation in most TC cells, but not in TPC-1 cells with RET/PTC1 rearrangement. Here, we show that depletion of RAF-1, a RAF family member with a poorly defined role in TC, decreases proliferation and increases apoptosis in TPC-1 cells and, less significantly, in cells harboring a BRAF(V600E) or HRAS(G13R) mutations, but without affecting ERR activation. We further demonstrate that constitutive activation of ERKs in TPC-1 cells is not caused by mutations in 50 oncogenes and tumor suppressors prone to activate the ERR pathway, or affected by inhibition of BRAF, MEK1/2 or PI3K. Our data indicate that RAF-1 is important for the survival of TPC-1 cells independently of the classical MEK1/2-ERK activation, offering new perspectives on RET/PTC signaling and for the therapy of thyroid cancers. (C) 2015 Elsevier Ireland Ltd. All rights reserved.