MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis.
MCPIP1-mediated NFIC alternative splicing inhibits proliferation of triple-negative breast cancer via cyclin D1-Rb-E2F1 axis.
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DOI：
10.1038/s41419-021-03661-4
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发表时间：
2021-04-06
影响因子：
9
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Chen F;Wang Q;Yu X;Yang N;Wang Y;Zeng Y;Zheng Z;Zhou F;Zhou Y
三阴性乳腺癌（TNBC）是最具侵袭性、预后最差、转移和复发潜力最高的亚型，占中国女性所有乳腺癌的15-20%，中国女性的5年总生存率约为80%。近年来，越来越多的证据表明，异常的选择性剪接（AS）在肿瘤的发生和发展中起着至关重要的作用。AS通常由AS相关的RNA结合蛋白（RBP）控制。单核细胞趋化蛋白诱导蛋白1（MCPIP 1）是一种锌指RBP，在许多癌症中起到肿瘤抑制剂的作用。在这里，我们发现MCPIP 1在80个TNBC组织和5个TNBC细胞系中与邻近癌旁组织和一个人永生化乳腺上皮细胞系相比下调，而其高表达水平与TNBC患者的总生存率增加相关。我们证明了MCPIP 1过表达在体外显著抑制TNBC细胞的细胞周期进展和增殖，并在体内抑制肿瘤生长。在机制上，MCPIP 1首先被证明作为剪接因子调节TNBC细胞中的AS。此外，我们证明了MCPIP 1调节NFIC AS以促进CTF 5合成，CTF 5在TNBC细胞中充当负调节剂。随后，我们发现CTF 5通过转录抑制cyclin D1的表达以及下调其下游信号靶点p-Rb和E2 F1参与了MCPIP 1介导的抗增殖作用。总之，我们的研究结果为MCPIP 1的抗癌机制提供了新的见解，表明MCPIP 1可以作为TNBC的替代治疗靶点。
Triple-negative breast cancer (TNBC) is the most aggressive subtype with the worst prognosis and the highest metastatic and recurrence potential, which represents 15–20% of all breast cancers in Chinese females, and the 5-year overall survival rate is about 80% in Chinese women. Recently, emerging evidence suggested that aberrant alternative splicing (AS) plays a crucial role in tumorigenesis and progression. AS is generally controlled by AS-associated RNA binding proteins (RBPs). Monocyte chemotactic protein induced protein 1 (MCPIP1), a zinc finger RBP, functions as a tumor suppressor in many cancers. Here, we showed that MCPIP1 was downregulated in 80 TNBC tissues and five TNBC cell lines compared to adjacent paracancerous tissues and one human immortalized breast epithelial cell line, while its high expression levels were associated with increased overall survival in TNBC patients. We demonstrated that MCPIP1 overexpression dramatically suppressed cell cycle progression and proliferation of TNBC cells in vitro and repressed tumor growth in vivo. Mechanistically, MCPIP1 was first demonstrated to act as a splicing factor to regulate AS in TNBC cells. Furthermore, we demonstrated that MCPIP1 modulated NFIC AS to promote CTF5 synthesis, which acted as a negative regulator in TNBC cells. Subsequently, we showed that CTF5 participated in MCPIP1-mediated antiproliferative effect by transcriptionally repressing cyclin D1 expression, as well as downregulating its downstream signaling targets p-Rb and E2F1. Conclusively, our findings provided novel insights into the anti-oncogenic mechanism of MCPIP1, suggesting that MCPIP1 could serve as an alternative treatment target in TNBC.
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影响因子：
5.7
作者：
Chen, Jun;Kinoshita, Taisei;Elias, Laurence
通讯作者：
Elias, Laurence
影响因子：
11.2
作者：
Lu W;Ning H;Gu L;Peng H;Wang Q;Hou R;Fu M;Hoft DF;Liu J
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影响因子：
254.7
作者：
DeSantis, Carol E.;Fedewa, Stacey A.;Jemal, Ahmedin
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Jemal, Ahmedin
影响因子：
16
作者：
Anczuków O;Akerman M;Cléry A;Wu J;Shen C;Shirole NH;Raimer A;Sun S;Jensen MA;Hua Y;Allain FH;Krainer AR
通讯作者：
Krainer AR
DOI：
10.1080/21691401.2019.1670670
发表时间：
2019-12-04
影响因子：
5.8
作者：
Li, Tianqi;Xiong, Yudi;Zhou, Yunfeng
通讯作者：
Zhou, Yunfeng