RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing.
RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing.
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DOI：
10.1038/s41388-021-01666-z
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发表时间：
2021-04
期刊：
影响因子：
8
通讯作者：
Chen C
中科院分区：
文献类型：
--
作者：
Yan Q;Zeng P;Zhou X;Zhao X;Chen R;Qiao J;Feng L;Zhu Z;Zhang G;Chen C
转移性膀胱癌(BCA)患者预后较差，目前的治疗方法不能改善其预后。RNA结合基序蛋白X连锁(RBMX)参与调节多种肿瘤的恶性进展。然而，RBMX在BCA肿瘤发生和发展中的作用仍不清楚。在这项研究中，我们发现RBMX在BCA组织中显著下调，特别是在肌肉侵袭性BCA组织中。RBMX的表达与肿瘤分期、组织学分级及预后不良呈负相关。功能分析表明，RBMX在体外抑制BCA细胞的增殖、集落形成、迁移和侵袭，在体内抑制肿瘤的生长和转移。机制研究表明，hnRNP A1是一种RBMX结合蛋白。RBMX竞争性抑制hnRNP A1中RGG基序与PKM外显子9两侧序列的结合，导致较低的PKM2和较高的PKM1水平，从而抑制BCA的致瘤性和进展。此外，RBMX通过依赖hnRNP A1的PKM选择性剪接抑制有氧糖酵解，并拮抗PKM2过表达诱导的BCA细胞的侵袭性表型。总之，我们的研究结果表明，RBMX通过hnRNP A1介导的PKM选择性剪接机制抑制BCA的肿瘤发生和进展。RBMX可作为临床干预BCA的一种新的预后生物标志物。
The prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.
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