UBAC2 promotes bladder cancer proliferation through BCRC-3/miRNA-182-5p/p27 axis
UBAC2 promotes bladder cancer proliferation through BCRC-3/miRNA-182-5p/p27 axis
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UBAC2通过BCRC-3/miRNA-182-5p/p27轴促进膀胱癌增殖
DOI：
10.1038/s41419-020-02935-7
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发表时间：
2020-09-10
影响因子：
9
通讯作者：
Jiang, Guosong
中科院分区：
文献类型：
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作者：
Gu, Chaohui;Zhao, Keyuan;Jiang, Guosong
越来越多的证据表明，泛素相关结构域蛋白2 （UBAC2）与恶性肿瘤的发生发展密切相关。然而，UBAC2在膀胱癌（BC）发展中的功能和潜在的分子机制尚未明确。在本研究中，我们发现UBAC2 mRNA和蛋白水平在BC组织和细胞系中均上调，UBAC2的下调在体外和体内均抑制了BC细胞的增殖。同时，TCGA数据库406例BC患者的Kaplan-Meier生存图显示，UBAC2在BC患者中的高表达与低生存率相关。机制研究表明，UBAC2的下调通过转录后调控增加了p27的表达。我们之前的研究表明，环状RNA BCRC-3 （BCRC-3）通过与miR-182-5p相互作用促进p27的表达，逆转miR-182-5p诱导的p27 3'UTR活性抑制。在本研究中，我们发现UBAC2可以结合BCRC-3，进而影响BCRC-3与miR-182-5p的相互作用，从而抑制p27的表达。此外，BCRC-3的敲低部分逆转了UBAC2敲低诱导的p27表达上调。本研究结果揭示了UBAC2通过影响BCRC-3功能调控p27的新机制，为BC的诊断和治疗应用提供了研究基础。
Emerging evidences have demonstrated that ubiquitin-associated domain-containing protein 2 (UBAC2) is closely related to the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of UBAC2 in bladder cancer (BC) development have not been defined. In this study, we found that both UBAC2 mRNA and protein levels were upregulated in BC tissues and cell lines, and knockdown of UBAC2 inhibited BC cells proliferation both in vitro and in vivo. Meanwhile, Kaplan–Meier survival plots of 406 BC cases from TCGA database showed that higher expression of UBAC2 in BC patients was associated with lower survival rate. Mechanistic studies revealed that knockdown of UBAC2 increased the expression of p27 by posttranscriptional regulation. Our previous study indicated that circular RNA BCRC-3 (BCRC-3) promoted the expression of p27 through interacting with miR-182-5p, and reversed miR-182-5p-induced inhibition of p27 3′UTR activity. In the present study, we found that UBAC2 could bind to BCRC-3, and subsequently affected the interaction of BCRC-3 with miR-182-5p to inhibit the expression of p27. Furthermore, knockdown of BCRC-3 partly reversed the upregulation of p27 expression induced by knockdown of UBAC2. Our findings highlight a novel mechanism of UBAC2 in regulating p27 through affecting the function of BCRC-3, and provide a research basis for the diagnostic and therapeutic application of BC.