Loss-of-function Mutations K11E or E271K Lead to Novel Tumor Suppression, Implicate Nucleolar Helicase DDX24 Oncogenicity.
Loss-of-function Mutations K11E or E271K Lead to Novel Tumor Suppression, Implicate Nucleolar Helicase DDX24 Oncogenicity.
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功能丧失突变 K11E 或 E271K 导致新的肿瘤抑制，涉及核仁解旋酶 DDX24 致癌性
DOI：
10.7150/ijms.67840
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发表时间：
2022
影响因子：
3.6
通讯作者：
Shan H
中科院分区：
文献类型：
--
作者：
Li X;Chen X;Gao J;Xian J;Li Z;Bi L;Yang M;Yang S;Jin H;Shan H
目的：DEAD-box RNA helicase 24（DDX 24）基因突变（K11 E或E271 K）与多器官静脉淋巴管畸形综合征（MOVLD）有关。然而，这些突变与DDX 24功能之间的关系仍然未知。了解K11 E和E271 K是否导致DDX 24的“功能丧失”或“功能获得”对于相关疾病具有重要意义。DDX 24与肿瘤关系密切，本研究旨在探讨K11 E和E271 K对DDX 24在肿瘤增殖中的作用。研究方法：基于中国仓鼠卵巢细胞（CHO）和Balb/c荷瘤小鼠模型，构建稳定表达野生型DDX 24、K11 E-DDX 24、E271 K-DDX 24、沿着仅载体的细胞系。然后进行免疫荧光染色、体外增殖实验、集落形成实验和18F-FDG PET/CT扫描。最后，收集肿瘤组织进行转录组测序，以预测潜在的机制。结果如下：CHO-WT-DDX 24、CHO-K11 E-DDX 24和CHO-E271 K-DDX 24处理后，细胞核数减少，增殖速度减慢，集落形成率降低。接种CHO-K11 E-DDX 24或CHO-E271 K-DDX 24细胞的小鼠皮下肿瘤的成瘤率较低，肿瘤生长速度较慢，预后较好，葡萄糖标准摄取值和Ki值降低。测序结果表明CHO-K11 E-DDX 24或CHO-E271 K-DDX 24引起TNF或趋化因子的表达增加以及免疫相关信号通路的改变。结论：K11 E或E271 K突变可导致DDX 24在细胞增殖和荷瘤小鼠中的“功能丧失”，可能通过非特异性免疫杀伤作用抑制肿瘤生长。
Purpose: Mutations (K11E or E271K) of DEAD-box RNA helicase 24 (DDX24) were related to multi-organ venous lymphatic malformation syndrome (MOVLD). However, the relationship between these mutations and DDX24-function still remains unknown. Understanding whether K11E and E271K cause “loss-of-function” or “gain-of-function” for DDX24 is significant for related diseases. DDX24 was reported to be related to tumors closely, thus this study aims to explore how K11E and E271K affect DDX24-function in tumor proliferation. Methods: Cell lines stably expressing wild-type DDX24, K11E-DDX24, E271K-DDX24, along with vector only based on Chinese hamster ovary cells (CHO) and Balb/c tumor-bearing mice models were constructed. Then immunofluorescence staining, proliferation assay and colony formation assay in vitro and 18F-FDG PET/CT-scan were performed. Finally, the tumor tissues were collected to perform transcriptome sequencing to predict the potential mechanism. Results: Contrasted with CHO-WT-DDX24, CHO-K11E-DDX24 or CHO-E271K-DDX24 showed a decreased number of nucleoli, a slower proliferation rate and a lower colony formation rate significantly. Moreover, mice, inoculated with CHO-K11E-DDX24 or CHO-E271K-DDX24 cells, showed lower tumor formation rate, slower tumor growth rate, better prognosis, reduced standard uptake value and Ki of glucose in subcutaneous tumors. Sequencing indicated CHO-K11E-DDX24 or CHO-E271K-DDX24 caused increasing expression of TNF or chemokines and alteration in immune-related signal pathways. Conclusion: K11E or E271K mutation could lead to “loss-of-function” of DDX24 in cell proliferation and tumor bearing mice, which may be acted by non-specific immune killing to inhibit tumor growth.
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影响因子：
8
作者：
Lindström MS;Jurada D;Bursac S;Orsolic I;Bartek J;Volarevic S
通讯作者：
Volarevic S
影响因子：
14.9
作者：
Larsen DH;Stucki M
通讯作者：
Stucki M
DOI：
10.1084/jem.138.5.1044
发表时间：
1973-11-01
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Loor F;Kindred B
通讯作者：
Kindred B
影响因子：
2.6
作者：
HINUMA, S;NARUO, K;TSUKAMOTO, K
通讯作者：
TSUKAMOTO, K
影响因子：
64.5
作者：
Feric M;Vaidya N;Harmon TS;Mitrea DM;Zhu L;Richardson TM;Kriwacki RW;Pappu RV;Brangwynne CP
通讯作者：
Brangwynne CP