CNOT1 cooperates with LMNA to aggravate osteosarcoma tumorigenesis through the Hedgehog signaling pathway.
CNOT1 cooperates with LMNA to aggravate osteosarcoma tumorigenesis through the Hedgehog signaling pathway.
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hocT1通过Hedgehog信号通路与LMNA协同作用加重骨肉瘤的肿瘤发生。
DOI：
10.1002/1878-0261.12043
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发表时间：
2017-04
影响因子：
6.6
通讯作者：
Fan CY
中科院分区：
文献类型：
--
作者：
Cheng DD;Li J;Li SJ;Yang QC;Fan CY
虽然儿童骨肉瘤的治疗方法有所改善，但这种常见类型的骨癌的总体生存率在三十年来没有改变，因此需要新的治疗靶点。为了鉴定骨肉瘤中的肿瘤相关蛋白，我们采用相对定量和绝对定量蛋白质组学方法，使用等压标签分析骨肉瘤细胞和人成骨细胞之间差异表达的蛋白。通过临床筛选和功能评估，发现CCR4-NOT转录复合物亚单位1 （CNOT1）与骨肉瘤细胞的生长相关。迄今为止，CNOT1在肿瘤（包括骨肉瘤）中的机制和调控作用在很大程度上仍然难以捉摸。在这里，我们提供的证据表明，在体外和体内，敲低CNOT1抑制骨肉瘤的生长。在机制上，我们观察到cnnot1与LMNA （lamin A）相互作用，并作为这种中间丝状蛋白的正调节因子。RNA‐seq分析显示，CNOT1缺失抑制了骨肉瘤细胞中的Hedgehog信号通路。一项救援研究表明，CNOT1缺失对骨肉瘤细胞生长的抑制和Hedgehog信号通路的抑制被LMNA过表达逆转，表明CNOT1的活性依赖于LMNA。值得注意的是，在骨肉瘤患者中，CNOT1的表达与肿瘤复发、Enneking分期和不良生存率显著相关。临床样本检测证实，CNOT1表达与LMNA蛋白表达呈正相关。综上所述，这些结果表明，CNOT1-LMNA-Hedgehog信号通路轴在骨肉瘤进展中发挥致癌作用，这可能是基因治疗的潜在靶点。
While treatments for childhood osteosarcoma have improved, the overall survival for this common type of bone cancer has not changed for three decades, and thus, new targets for therapeutic development are needed. To identify tumor‐related proteins in osteosarcoma, we used isobaric tags in a relative and absolute quantitation proteomic approach to analyze the differentially expressed proteins between osteosarcoma cells and human osteoblastic cells. Through clinical screening and functional evaluation, CCR4–NOT transcription complex subunit 1 (CNOT1) correlated with the growth of osteosarcoma cells. To date, the mechanisms and regulatory roles of CNOT1 in tumors, including osteosarcoma, remain largely elusive. Here, we present evidence that knockdown of CNOT1 inhibits the growth of osteosarcoma in vitro and in vivo. Mechanistically, we observed that CNOT1 interacted with LMNA (lamin A) and functioned as a positive regulator of this intermediate filament protein. The RNA‐seq analysis revealed that CNOT1 depletion inhibited the Hedgehog signaling pathway in osteosarcoma cells. A rescue study showed that the decreased growth of osteosarcoma cells and inhibition of the Hedgehog signaling pathway by CNOT1 depletion were reversed by LMNA overexpression, indicating that the activity of CNOT1 was LMNA dependent. Notably, the CNOT1 expression was significantly associated with tumor recurrence, Enneking stage, and poor survival in patients with osteosarcoma. Examination of clinical samples confirmed that CNOT1 expression positively correlated with LMNA protein expression. Taken together, these results suggest that the CNOT1–LMNA–Hedgehog signaling pathway axis exerts an oncogenic role in osteosarcoma progression, which could be a potential target for gene therapy.
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DOI：
10.1158/1078-0432.ccr-15-1468
发表时间：
2016-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Bell EH;Chakraborty AR;Mo X;Liu Z;Shilo K;Kirste S;Stegmaier P;McNulty M;Karachaliou N;Rosell R;Bepler G;Carbone DP;Chakravarti A
通讯作者：
Chakravarti A
影响因子：
7.8
作者：
Gibbs-Seymour I;Markiewicz E;Bekker-Jensen S;Mailand N;Hutchison CJ
通讯作者：
Hutchison CJ
影响因子：
4.4
作者：
Folio, Cecilia;Mora, Maria I.;Patino-Garcia, Ana
通讯作者：
Patino-Garcia, Ana
影响因子：
5
作者：
Jou, Yu-Jen;Hua, Chun-Hung;Lin, Cheng-Wen
通讯作者：
Lin, Cheng-Wen
影响因子：
37.3
作者：
Hirotsu M;Setoguchi T;Sasaki H;Matsunoshita Y;Gao H;Nagao H;Kunigou O;Komiya S
通讯作者：
Komiya S