Deregulation of CLTC interacts with TFG, facilitating osteosarcoma via the TGF-beta and AKT/mTOR signaling pathways.
Deregulation of CLTC interacts with TFG, facilitating osteosarcoma via the TGF-beta and AKT/mTOR signaling pathways.
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CLTC 的失调与 TFG 相互作用，通过 TGF-β 和 AKT/mTOR 信号通路促进骨肉瘤
DOI：
10.1002/ctm2.377
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发表时间：
2021-06
影响因子：
10.6
通讯作者：
Dongdong C
中科院分区：
文献类型：
--
作者：
Shijie L;Zhen P;Kang Q;Hua G;Qingcheng Y;Dongdong C
尽管骨肉瘤的治疗有所改善，但这种常见类型的骨恶性肿瘤的总体存活率40年来没有变化。因此，迫切需要更好的治疗方案的新目标。在本研究中，我们发现笼状蛋白重链的高表达是骨肉瘤患者无瘤生存期(HzR，3.049；95%CI，1.476-6.301)和总生存期(HzR，2.469；95%CI，1.005-6.067)的独立预后因素。在体外和体内，下调Cltc的表达可导致肿瘤抑制作用。此外，我们还发现Cltc受转录因子特异性蛋白1(Sp1)的转录调控，该转录因子特异性蛋白1结合在−320~−314-nt和+167~+173-nt位点的Cltc启动子上。机制研究进一步表明，Cltc通过直接与内质网结合并稳定从内质网到高尔基体调节器(TFG)的运输而产生促肿瘤作用。重要的是，TfG的过表达挽救了由Cltc下调所引起的对转化生长因子-β和AKT/mTor通路的抑制作用，这表明Cltc的活性是Tfg依赖的。免疫组织化学分析证实，Cltc表达与TFG表达呈正相关。这些发现共同强调了Cltc是骨肉瘤患者的一个新的预后生物标志物，而SP1/Cltc/TFG轴的阻断可能成为骨肉瘤的一种新的治疗策略。1.在骨肉瘤患者中，Cltc高表达与临床预后不良相关。2.Cltc抑制骨肉瘤的体外和体内生长。3.SP1与Cltc启动子结合，促进骨肉瘤中Cltc的转录活性。4.Cltc通过激活TFG依赖的转化生长因子-β和AKT/mTOR信号通路发挥致癌作用。
Although the treatment of osteosarcoma has improved, the overall survival rate of this common type of osseous malignancies has not changed for four decades. Thus, new targets for better therapeutic regimens are urgently needed. In this study, we found that high expression of clathrin heavy chain (CLTC) was an independent prognostic factor for tumor‐free survival (HzR, 3.049; 95% CI, 1.476–6.301) and overall survival (HzR, 2.469; 95% CI, 1.005–6.067) of patients with osteosarcoma. Down‐regulation of CLTC resulted in tumor‐suppressive effects in vitro and in vivo. Moreover, we found that CLTC was transcriptionally regulated by a transcription factor—specificity protein 1 (SP1), which binds to the CLTC promoter at the −320 to −314‐nt and +167 to +173‐nt loci. Mechanistic investigations further revealed that CLTC elicited its pro‐tumor effects by directly binding to and stabilizing trafficking from the endoplasmic reticulum to the Golgi regulator (TFG). Importantly, overexpression of TFG rescued both the tumor‐suppressive effect and inhibition of the TGF‐β and AKT/mTOR pathways caused by CLTC down‐regulation, which indicated that the activity of CLTC was TFG‐dependent. Immunohistochemistry analysis confirmed that CLTC expression was positively correlated with TFG expression. These findings collectively highlight CLTC as a new prognostic biomarker for patients with osteosarcoma, and the interruption of the SP1/CLTC/TFG axis may serve as a novel therapeutic strategy for osteosarcoma. 1. High CLTC expression is associated with worse clinical outcomes in osteosarcoma patients. 2. Inhibition of CLTC suppresses osteosarcoma growth both in vitro and in vivo. 3. SP1 binds to the CLTC promoter to promote the transcriptional activity of CLTC in osteosarcoma. 4. CLTC‐mediated oncogenic effects occurred through activation of the TGF‐beta and AKT/mTOR signaling pathway in a TFG‐dependent manner.
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影响因子：
37.3
作者：
Huang MD;Chen WM;Qi FZ;Sun M;Xu TP;Ma P;Shu YQ
通讯作者：
Shu YQ
DOI：
10.1080/15384101.2020.1805552
发表时间：
2020-09
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Ma K;Zhang C;Li W
通讯作者：
Li W
影响因子：
11.2
作者：
Kong, Ling-Min;Liao, Cheng-Gong;Chen, Zhi-Nan
通讯作者：
Chen, Zhi-Nan
影响因子：
8
作者：
Maurizi G;Verma N;Gadi A;Mansukhani A;Basilico C
通讯作者：
Basilico C
影响因子：
3.7
作者：
Cools, J;Wlodarska, I;Marynen, P
通讯作者：
Marynen, P