The Central Laboratory of Shantou University Medical Cancer Hospital College, Shantou, China.
J Cell Mol Med. 2020 Jan;24(1):1116-1127. doi: 10.1111/jcmm.14849. Epub 2019 Nov 21.
Adipocytes constitute a major component of the tumour microenvironment. Numerous studies have shown that adipocytes promote aggressiveness and invasion by stimulating cancer cells proliferation and modulating their metabolism. Herein, we reported that Notch3 promotes mouse 3T3-L1 pre-adipocytes differentiation by performing the integrative transcriptome and TMT-based proteomic analyses. The results revealed that aminoacyl-tRNA_biosynthesis pathway was significantly influenced with Nocth3 change during 3T3-L1 pre-adipocytes differentiation, and the expression of LARS in this pathway was positively correlated with Notch3. Published studies have shown that LARS is a sensor of leucine that regulates the mTOR pathway activity, and the latter involves in adipogenesis. We therefore supposed that Notch3 might promote 3T3-L1 pre-adipocytes differentiation by up-regulating LARS expression and activating mTOR pathway. CHIP and luciferase activity assay uncovered that Notch3 could transcriptionally regulate the expression of LARS gene. Oil Red staining identified a positive correlation between Notch3 expression and adipocytic differentiation. The activation of mTOR pathway caused by Notch3 overexpression could be attenuated by knocking down LARS expression. Altogether, our study revealed that Notch3 promotes adipocytic differentiation of 3T3-L1 pre-adipocytes cells by up-regulating LARS expression and activating the mTOR pathway, which might be an emerging target for obesity treatment.
脂肪细胞构成肿瘤微环境的主要成分。许多研究表明，脂肪细胞通过刺激癌细胞增殖和调节其代谢来促进侵袭和侵袭。在此，我们通过整合转录组和基于 TMT 的蛋白质组学分析报告了 Notch3 通过促进小鼠 3T3-L1 前脂肪细胞分化。结果表明，在 3T3-L1 前脂肪细胞分化过程中，Notch3 变化明显影响了氨基酸酰-tRNA 合成途径，并且该途径中的 LARS 表达与 Notch3 呈正相关。已发表的研究表明，LARS 是亮氨酸的传感器，可调节 mTOR 途径的活性，后者参与脂肪生成。因此，我们推测 Notch3 可能通过上调 LARS 表达和激活 mTOR 途径来促进 3T3-L1 前脂肪细胞的分化。CHIP 和荧光素酶活性测定揭示了 Notch3 可以转录调控 LARS 基因的表达。油红染色鉴定了 Notch3 表达与脂肪细胞分化之间的正相关关系。Notch3 过表达引起的 mTOR 途径的激活可以通过敲低 LARS 表达来减弱。总的来说，我们的研究表明，Notch3 通过上调 LARS 表达和激活 mTOR 途径促进 3T3-L1 前脂肪细胞的脂肪细胞分化，这可能成为肥胖治疗的新靶点。
