Roles of TGFβ1 in the expression of phosphoinositide 3-kinase isoform genes and sensitivity and response of lung telocytes to PI3K inhibitors
Roles of TGFβ1 in the expression of phosphoinositide 3-kinase isoform genes and sensitivity and response of lung telocytes to PI3K inhibitors
复制标题
TGFβ1 在磷酸肌醇 3 激酶亚型基因表达以及肺特细胞对 PI3K 抑制剂的敏感性和反应中的作用
DOI：
10.1007/s10565-019-09487-3
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发表时间：
2020-02-01
影响因子：
6.1
通讯作者：
Wang, Xiangdong
中科院分区：
文献类型：
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作者：
Song, Dongli;Tang, Li;Wang, Xiangdong
背景最近建立的小鼠肺远程细胞系（TCSV40）为了解TC生物学和功能提供了进一步的机会。本研究旨在研究磷酸肌醇3激酶（PI3K）亚型在TC增殖和运动以及TGFβ1诱导的肺TC对PI3K抑制剂的敏感性和反应中的调节作用。材料和方法定义了小鼠原代TC中编码PI3K家族或TGFβ家族蛋白的基因的网络和分子相互作用。在有或没有 TGFβ1 刺激或 PI3K 催化亚型蛋白（PI3K/mTOR、PI3Kα/δ/β、PI3K p110δ 或 pan-PI3K）抑制的情况下测量小鼠肺 TCSV40 增殖、细胞凋亡、细胞周期和动态生物行为。结果本研究显示了原发性肺中编码 PI3K 亚型蛋白或 TGFβ 家族蛋白的基因的网络特征和相互作用的差异小鼠肺部的远程细胞与肺部其他细胞的比较。 TGFβ1 对 TC 增殖具有不同的影响，G2 或 S 期的 TC 数量发生改变，与 TGFβ1 的给药剂量无关。 PI3Kα/δ/β、PI3K/mTOR、PI3K p110δ参与TC增殖，其中PI3Kα/δ/β较敏感。 pan-PI3K 抑制剂的作用表明，更多的 PI3K 亚型受到外部 TGFβ1 的刺激，并有助于 TGFβ1 诱导的 TC 增殖。 PI3K p110δ 在没有 TGFβ1 的情况下动态上调 TC 增殖和运动，并且在 TGFβ1 刺激下下调 TC 增殖，但不下调 TC 运动。 PI3Kα/δ/β和PI3K/mTOR在TGFβ1诱导的S期积累中更活跃，并且与PI3K p110δ具有相似的动态效应。 TGFβ1 刺激后，TC 中 PI3K 亚型的基因表达上调。当抑制 PI3K/mTOR、PI3Kα/δ/β、PI3K p110δ 或 pan-PI3K 时，在不含 TGFβ1 的 TC 中，编码 p110-α 的 PIK3CA 或编码 p110-γ 的 PIK3CG 的表达分别上调或下调。 TGFβ1上调PIK3CA和PIK3CB的表达，同时下调PIK3CD和PIK3CG的表达。结论我们的数据表明，TGFβ1在肺TC中PI3K亚型基因的表达中发挥不同的作用，并且可以改变肺TC对PI3K抑制剂的敏感性和反应。
BackgroundThe mouse lung telocyte cell line (TCSV40) recently established provides further opportunities to learn TC biology and functions. The present study aims at investigating regulatory roles of phosphoinositide 3-kinase (PI3K) isoforms in TC proliferation and movement and in TGFβ1-induced sensitivity and response of lung TCs to PI3K inhibitors.Materials and methodsNetwork and molecular interactions of genes coding PI3K family or TGFβ family proteins in mouse primary TCs were defined. Mouse lung TCSV40proliferation, apoptosis, cell cycle, and dynamical bio-behaviors were measured with or without TGFβ1 stimulation or PI3K catalytic isoform protein (PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K) inhibitions.ResultsThe present study showed the difference of network characteristics and interactions of genes coding PI3K isoform proteins or TGFβ family proteins in primary lung telocytes from mouse lungs compared to those of other cells residing in the lung. TGFβ1 had diverse effects on TC proliferation with altered TC number in G2 or S phase, independent upon the administered dose of TGFβ1. PI3Kα/δ/β, PI3K/mTOR, and PI3K p110δ were involved in TC proliferation, of which PI3Kα/δ/β was more sensitive. The effects of pan-PI3K inhibitor indicate that more PI3K isoforms were stimulated by the administering of external TGFβ1 and contributed to TGFβ1-induced TC proliferation. PI3K p110δ upregulated TC proliferation and movement dynamically without TGFβ1, and downregulated TC proliferation with TGFβ1 stimulation, but not TC movement. PI3Kα/δ/β and PI3K/mTOR were more active in TGFβ1-induced S phase accumulation and had similar dynamic effects to PI3K p110δ. Gene expression of PI3K isoforms in TCs was upregulated after TGFβ1 stimulation. The expression of PIK3CA coding p110-α or PIK3CG coding p110-γ were up- or downregulated in TCs without TGFβ1, respectively, when PI3K/mTOR, PI3Kα/δ/β, PI3K p110δ, or pan-PI3K were inhibited. TGFβ1 upregulated the expression of PIK3CA and PIK3CB, while downregulated the expression of PIK3CD and PIK3CG.ConclusionOur data imply that TGFβ1 plays divergent roles in the expression of PI3K isoform genes in lung TCs and can alter the sensitivity and response of lung TCs to PI3K inhibitors.