CircNUP54 promotes hepatocellular carcinoma progression via facilitating HuR cytoplasmic export and stabilizing BIRC3 mRNA

Sep 21, 2026

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Circular RNAs (circRNAs) are frequently linked to cancer development, yet their mechanisms in hepatocellular carcinoma (HCC) are not fully defined. This study identifies the oncogenic circRNA hsa_circ_0070039 (circNUP54) as markedly upregulated in HCC. In 68 patient samples, circNUP54 elevation associates with aggressive phenotypes and poor prognosis. Functional assays show circNUP54 knockdown suppresses HCC malignancy in vitro and in vivo, while overexpression enhances progression. Mechanistically, circNUP54 binds HuR, promotes its cytoplasmic export, stabilizes BIRC3 mRNA, and activates NF-κB signaling via cIAP2. BIRC3 depletion reverses circNUP54-driven protumor effects.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

CircRNAs in cancer and HCC

CircRNAs as microRNA sponges

CircRNAs cooperating with RNA-binding proteins (RBPs)

HuR (ELAVL1) as a key RBP in tumor biology

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN CircNUP54 promotes hepatocellular carcinoma progression via facilitating HuR cytoplasmic export and stabilizing BIRC3 mRNA Chenwei Tang 1,2,5, Hongkai Zhuang 1,2,5, Wentao Wang 1,2, Qingbin Wang1,2, Xiaowu Ma1,2, Bingkun Wang1,2, Ziyu Zhang 1,2, Jiahao Jiang 1,2, Zhiqin Xie3, Wenliang Tan3, Lei Yang1,2, Songyao Liu1,2, Yonglin Hua 1,2, Yuxin Xiao1,2, Baoshan Ding4, Yajin Chen1,2 ✉ and Changzhen Shang 1,2 ✉ © The Author(s) 2024 | | Circular RNAs (circRNAs) have been implicated in tumorigenesis and progression of various cancers. However, the underlying mechanisms of circRNAs in hepatocellular carcinoma (HCC) have not been fully elucidated. Herein, a new oncogenic circRNA, hsa_circ_ 0070039 (circNUP54), was identiﬁed to be signiﬁcantly upregulated in HCC through circRNA sequencing. As veriﬁed in 68 HCC samples, circNUP54 overexpression was correlated with aggressive cancerous behaviors and poor outcomes. Moreover, the function experiments showed that knockdown of circNUP54 inhibited the malignant progression of HCC in vitro and in vivo, whereas overexpression of circNUP54 had the opposite role. Mechanistic investigations carried out by RNA pull-down, RNA immunoprecipitation, and immunoﬂuorescence revealed that circNUP54 interacted with the RNA-binding protein Hu-antigen R (HuR) and promoted its cytoplasmic export. The cytoplasmic accumulation of HuR stabilized the downstream BIRC3 mRNA through its binding to the 3′ UTR region. Consequently, the encoded protein of BIRC3, cellular inhibitor of apoptosis 2 (cIAP2), proceeded to activate the NF-κB signal pathway and ultimately contributed to HCC progression. In addition, depletion of BIRC3 rescued the protumorigenic effect of circNUP54 on HCC cells. Overall, this study demonstrated that circNUP54 facilitates HCC progression via | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | regulating the HuR/BIRC3/NF-κB axis, which may serve as a promising therapeutic target for HCC treatment. | | | | | Cell Death and Disease (2024)15:191; [https://doi.org/10.1038/s41419-024-06570-4](https://doi.org/10.1038/s41419-024-06570-4) | | | | | | INTRODUCTION Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related mortality worldwide [1]. Hepatocellular carcinoma (HCC) is the most common primary liver cancer, accounting for 85–90% of all cases [2]. Owing to the insidious onset of HCC, a substantial proportion of patients are diagnosed atan advanced stage and are unsuitable for radical resection [3]. Despite signiﬁcant improvements in both surgical and pharmacological treatments, the prognosis of patients with HCC remains poor [4]. Therefore, in-depth investigation into the molecular mechanisms underlying tumorigenesis and progression is essential to uncovering new therapeutic targets for HCC. Circular RNAs (circRNAs) are a special class of non-coding RNAs characterized by a covalently closed single-stranded circular structure that are produced by back-splicing of exons, introns, or untranslated regions [5, 6]. Aberrant circRNA expression plays a regulatory role in intracellular signal transduction, which contributes to the tumorigenesis of many cancers [7], including breast cancer [8], non-small cell lung cancer [9], and gastric cancer [10]. Generally, most circRNAs exert their functions by sponging microRNAs (miRNAs), which means reducing the repression effect of miRNAs on the targeted mRNA [11]. For instance, circANAPC7 sponges miR-373 to suppress pancreatic cancer [12]. Regarding HCC, many circRNAs, such as hsa_-circ_ 0072309 [13], hsa_circ_ 0007874 [14], and hsa_circ_0095868 [15], have been identiﬁed as miRNA sponges that participate in oncogenesis, progression, and drug resistance of HCC. However, the additional potential mechanisms of action of circRNAs in HCC rem

FAQs

What is the main role of circNUP54 in hepatocellular carcinoma?

circNUP54 promotes HCC progression. Its knockdown inhibits malignant progression, while overexpression enhances aggressive behaviors.

How does circNUP54 affect HuR activity?

circNUP54 interacts with HuR and promotes its export to the cytoplasm, increasing cytoplasmic HuR accumulation.

What downstream pathway links circNUP54 to tumor progression?

Cytoplasmic HuR stabilizes BIRC3 mRNA via binding to its 3′ UTR, leading to cIAP2 production that activates NF-κB signaling, supporting HCC progression.

Sep 21, 2026

Uploaded by Finn