The ncRNA-AURKA Interaction in Hepatocellular Carcinoma: Insights into Oncogenic Pathways, Therapeutic Opportunities, and Future Challenges

Abstract

Hepatocellular carcinoma (HCC) represents a major public health concern and ranks among the leading cancer-related mortalities globally. Due to the frequent late-stage diagnosis of HCC, therapeutic options remain limited. Emerging evidence highlights the critical role of non-coding RNAs (ncRNAs) in the regulation of Aurora kinase A (AURKA), one of the key hub genes involved in several key cancer pathways. Indeed, the dysregulated interaction between ncRNAs and AURKA contributes to tumor development, progression, and therapeutic resistance. This review delves into the interplay between ncRNAs and AURKA and their role in hepatocarcinogenesis. Recent findings underscore the involvement of the ncRNAs and AURKA axis in tumor development and progression. Furthermore, this review also discusses the clinical significance of targeting ncRNA-AURKA axes, offering new perspectives that could lead to innovative therapeutic strategies aimed at improving outcomes for HCC patients.

Keywords: Aurora kinase A; circular RNA; hepatocellular carcinoma; long-non-coding RNA; microRNA.

Figure 3

The regulatory network of AURKA and ncRNAs in HCC. Regulatory ncRNAs influence the expression of AURKA both at the mRNA and protein levels in HCC. MiRNAs targeting AURKA, such as miR-199-3p [96], miR-124-3p [92], miR-490-3p [89], miR-129-3p [99], and miR-26a-5p [101], are frequently downregulated in HCC. Transcriptomic analyses revealed upregulation of miR-1269b, miR-518d, and miR-6728 and downregulation of miR-139 and miR-4800 [95]. AURKA indirectly upregulates miR-21 expression by activating NF-κB signaling. The p50/p65 complex binds to the miR-21 promoter sequence, thus promoting its transcription. In turn, miR-21 represses PTEN, the negative regulator of the PI3K/AKT pathway [24]. LncRNAs such as MALAT1 [104] and TUG1 [105] and the circRNA circHMGS1 [106] positively regulate AURKA expression, while KDM4A-AS1 forms a complex with ILF3 to recruit and stabilize AURKA [20]. M6A-mediated hypermethylation of TIALD1 effectively blocks AURKA protein from lysosomal degradation [107].

Figure 1

The multifaceted roles of AURKA. Under physiological conditions (green), AURKA plays a key function in mitotic progression, including G2/M checkpoint release, mitotic spindle formation, organization, and epigenetic regulation. It also contributes to the disassembly of primary cilia, initiation of DNA replication, and regulation of mitochondrial fission and energy production. AURKA interacts with numerous proteins and participates in diverse signaling pathways; thus, its overexpression in cancer leads to the dysregulation of these pathways, driving oncogenic effects. In the context of cancer (red), AURKA enhances cell survival and proliferation, epithelial-mesenchymal transition (EMT), and cancer invasiveness.

Figure 2

Regulatory ncRNAs: From physiology to pathology. Regulatory ncRNAs are a fraction of the ncRNAs within the human genome. MicroRNAs (miRNAs), long-non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are the major players involved in regulating gene expression and protein levels and stability in physiological and pathological conditions.