YAP/miR-524-5p axis negatively regulates TXNIP expression to promote chondrosarcoma cell growth
YAP/miR-524-5p axis negatively regulates TXNIP expression to promote chondrosarcoma cell growth
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YAP/miR-524-5p轴负调控TXNIP表达促进软骨肉瘤细胞生长
DOI：
10.1016/j.bbrc.2021.12.052
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发表时间：
2022
影响因子：
3.1
通讯作者：
Jing-Xiang Li
中科院分区：
文献类型：
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作者：
Ri-Xu Liu;Wang Tang;Bo-Yuan Zheng;Yong Yang;Zhen-Yan Li;Tao Gui;Huan-Tian Zhang;Ning Liu;Zhen-Gang Zha;Jing-Xiang Li
软骨肉瘤（CHS）是第二常见的骨恶性肿瘤，目前治疗选择有限。我们最近发现硫氧还蛋白相互作用蛋白（TXNIP）在骨肉瘤的肿瘤发生中起着至关重要的作用，但其在CHS中的意义尚不明确。在本研究中，我们首次发现TXNIP基因敲低后促进CHS细胞增殖的机制主要是通过增加细胞的糖酵解代谢，即所谓的瓦尔堡效应提供能量。与我们先前报道的雅普是CHS细胞生长的基础相一致，我们在此揭示了雅普作为TXNIP的上游分子，并且雅普在体外和体内均负调控TXNIP mRNA和蛋白的表达。从机制上讲，虽然敲低雅普上调了细胞核和细胞质的TXNIP表达，但我们没有观察到雅普和TXNIP之间的任何明显的相互作用;相反，miRNA-524- 5 p被证明是YAP调节的TXNIP表达所必需的，从而控制CHS细胞生长。总之，我们的研究揭示了TXNIP是CHS的肿瘤抑制剂，并且雅普/miRNA-524- 5 p/TXNIP信号传导轴可能为CHS靶向治疗提供新的线索。
Chondrosarcoma (CHS) is the second most common bone malignant tumor and currently has limited treatment options. We have recently demonstrated that thioredoxin interacting protein (TXNIP) plays a crucial role in the oncogenesis of bone sarcoma, yet its implication in CHS is underdetermined. In the present study, we first found that knockdown of TXNIP promotes the proliferation of CHS cell largely through increasing their glycolytic metabolism, which is well-known as Warburg effect for providing energy. Consistent with our previous report that YAP is fundamental for CHS cell growth, herein we revealed that YAP functioned as an upstream molecule of TXNIP, and that YAP negatively regulated TXNIP mRNA and protein expression bothin vitroandin vivo. Mechanistically, although knockdown of YAP upregulated both the nuclear and cytoplasmic TXNIP expression, we did not observe any obvious interaction between YAP and TXNIP; instead, miRNA-524-5p was demonstrated to be required for YAP-regulated TXNIP expression and thus controlling CHS cell growth. Together, our study reveals that TXNIP is a tumor suppressor in terms of CHS, and that the YAP/miRNA-524-5p/TXNIP signaling axis may provide a novel clue for CHS targeted therapy.