Nuclear paraspeckle assembly transcript 1: The long non-cognized RNA connecting senescence and hepatocellular carcinoma

Liver cancer is a major global healthcare challenge and its incidence is growing worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and contributes to about 90% of cases.¹ While a broad range of treatment opinions is currently available for patients with HCC, including surgical interventions (such as liver resection or transplantation), ablation, intra-arterial therapies, radiotherapy and systemic therapies,² the post-treatment metastasis or recurrence rates remain notably high.³ Therefore, there is an urgent need to investigate the molecular mechanisms driving HCC tumorigenesis and development to enhance treatment strategies.

Senescence represents a cellular response to various stress signals, involving a stable withdrawal from the cell cycle and significant alterations in cell morphology and physiology, this phenomenon emerges as a potential double-edged sword in the context of both cancer and its treatment.⁴ Senescent somatic cells, senescence bypass and senescence-associated secretory phenotype (SASP) correlate with tumorigenesis and recurrence.⁵ Conversely, the characteristics of cellular senescence in cancer cells, encompassing growth arrest and immunomodulatory features, are associated with potent anti-cancer roles.^{6, 7} Therapeutic intervention-induced SASP of senescent cancer cells has also demonstrated an anti-tumor effect.⁸ However, the regulatory mechanisms of cancer cell senescence remain poorly understood, limiting the development of anti-cancer strategies targeting cellular senescence in cancer cells.

Accumulating evidence has recently demonstrated the important role of long noncoding RNAs (lncRNAs) in the tumorigenesis, progression and treatment of HCC. Numerous HCC-related lncRNAs exhibit aberrant expression patterns and could regulate cell proliferation, apoptosis and invasion through interacting with nucleic acids or proteins.^9-11 In a recent study by Chen et al., a novel connection was uncovered between the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), senescence and hepatocellular carcinoma (Figure 1).¹² The researchers found that NEAT1 was expressed at high levels in both HCC tissues and hepatoma cells, showing a negative correlation with senescence in HCC. Under the condition of reactive oxygen species (ROS)-induced cellular senescence in hepatoma cells, NEAT1 was released from paraspeckles and translocated from the nucleus to the cytoplasm, where it interacted with kinesin family member 11 (KIF11) and facilitated its degradation.

As illustrated in Figure 1, a similar nuclear translocation of NEAT1 has been observed in activated macrophages. Cytoplasmic NEAT1 has been identified to enhance the activation and assembly of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, triggering a robust inflammatory response and promoting pyroptosis, as reported in their previous study.¹³ In recent years, a growing body of research has highlighted the close association between the subcellular localization of lncRNAs and their biological functions in cancer.¹⁴ The series of studies on the nuclear translocation and molecular mechanisms of NEAT1 provide new insights into how cells employ this intricate molecular function to respond to external stimuli and finely regulate cellular functions. Following this, Chen et al. demonstrated that the deficiency of KIF11 leads to the transcriptional activation and DNA demethylation of Cyclin-Dependent Kinase Inhibitor 2A, processes mediated respectively by Wingless-INT and Tet methylcytosine dioxygenase 2. Consequently, this results in the upregulation of the p16^INK4A and p14^ARF signalling pathways. Finally, depletion of NEAT1 or KIF11 resulted in senescence and impeded the progression of hepatocellular carcinoma in mouse models. In summary, the comprehensive and intriguing findings presented in this study unveil novel mechanisms underlying cellular senescence in cancer cells, with a particular emphasis on HCC.

The concept of “one-two punch” cancer therapy, involving the induction of tumour cell senescence followed by selective clearance, has emerged as a strategy to enhance treatment outcomes for cancer patients.¹⁵ However, the current status of “one-two punch” therapy remains experimental, and confined to animal studies, and further preclinical trials are essential to determine its clinical efficacy in inhibiting the development of hepatocellular carcinoma.¹⁶ Chen et al. utilized a combination of cell models, mouse models and clinical samples from HCC patients to demonstrate that inhibiting NEAT1 or KIF11, along with serum starvation, H₂O₂, or doxorubicin treatment, induces senescence and restricts HCC progression. Future research should explore the inhibitory effect of ROS-inducing cell senescence on HCC development using organoid models or patient-derived xenograft models. Furthermore, additional molecular mechanisms underlying this process should be elucidated. Additionally, further investigation is needed to understand how to effectively eliminate these senescent cells in later stages, aiming to achieve the goal of a radical treatment for HCC.

In summary, the study by Chen et al. suggests the potential therapeutic significance of targeting NEAT1 or KIF11 to induce cellular senescence as a strategy for limiting the development of hepatocellular carcinoma.¹²

Drs. Wu, Zhou, Zhou and Xu contributed to the preparation and collection of original literature and figures and the writing and editing of the manuscript.

The authors declare no conflict of interest.

Not applicable.