RANBP1 promotes colorectal cancer progression by regulating pre-miRNA nuclear export via a positive feedback loop with YAP
RANBP1 promotes colorectal cancer progression by regulating pre-miRNA nuclear export via a positive feedback loop with YAP
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DOI：
10.1038/s41388-021-02036-5
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发表时间：
2021-10
期刊：
影响因子：
8
通讯作者：
D. Zheng;M. Cao;Siyu Zuo;Xin Xia;Chu Zhi;Yanbing Lin;Sitong Deng;Xiaoqin Yuan
中科院分区：
文献类型：
--
作者：
D. Zheng;M. Cao;Siyu Zuo;Xin Xia;Chu Zhi;Yanbing Lin;Sitong Deng;Xiaoqin Yuan
结直肠癌（CRC）是全球最常见的五种恶性肿瘤之一，死亡率很高。确定 CRC 的机制和潜在的治疗靶点对于提高生存率至关重要。在本研究中，我们观察到 RAN 结合蛋白 1 (RANBP1) 在 CRC 组织中高表达。 RANBP1表达上调与TNM分期密切相关，是不良预后的独立危险因素。体外和体内功能实验表明，RANBP1促进CRC细胞的增殖和侵袭，抑制CRC细胞的凋亡。 RANBP1低表达通过抑制前体miRNA（pre-miRNA）的核质转运，降低hsa-miR-18a、hsa-miR-183和hsa-miR-106 microRNA（miRNA）的表达水平，从而促进后者在细胞核中的积累并减少成熟miRNA的表达。进一步的实验和生物信息分析表明，RANBP1通过调节miRNA和Hippo通路来促进YAP的表达。我们还发现 YAP 作为转录辅助因子与 TEAD4 转录因子结合激活 RANBP1 转录。因此，RANBP1通过与YAP形成正反馈环进一步促进了CRC的进展。我们的研究结果首次揭示了RANBP1在CRC中的生物学作用和机制，表明RANBP1可以作为CRC的诊断分子和潜在的治疗靶点。
Colorectal cancer (CRC) is among the top five most common malignant tumors worldwide and has a high mortality rate. Identification of the mechanism of CRC and potential therapeutic targets is critical for improving survival. In the present study, we observed high expression of RAN binding protein 1 (RANBP1) in CRC tissues. Upregulated RANBP1 expression was strongly associated with TNM stages and was an independent risk factor for poor prognosis. In vitro and in vivo functional experiments demonstrated that RANBP1 promoted the proliferation and invasion of CRC cells and inhibited the apoptosis of CRC cells. Low RANBP1 expression reduced the expression levels of hsa-miR-18a, hsa-miR-183, and hsa-miR-106 microRNAs (miRNAs) by inhibiting the nucleoplasmic transport of precursor miRNAs (pre-miRNAs), thereby promoting the accumulation of the latter in the nucleus and reducing the expression of mature miRNAs. Further experiments and bioinformatic analyses demonstrated that RANBP1 promoted the expression of YAP by regulating miRNAs and the Hippo pathway. We also found that YAP acted as a transcriptional cofactor to activate RANBP1 transcription in combination with TEAD4 transcription factor. Thus, RANBP1 further promoted the progression of CRC by forming a positive feedback loop with YAP. Our results revealed the biological role and mechanism of RANBP1 in CRC for the first time, suggesting that RANBP1 can be used as a diagnostic molecule and a potential therapeutic target in CRC.