Significance of nucleologenesis, ribogenesis, and nucleolar proteome in the pathogenesis and recurrence of hepatocellular carcinoma

Emerging evidence suggests that enhanced ribosome biogenesis, increased size, and quantitative distribution of nucleoli are associated with dysregulated transcription, which in turn drives a cell into aberrant cellular proliferation and malignancy. Nucleolar alterations have been considered a prognostic histological marker for aggressive tumors. More recently, advancements in the understanding of chromatin network (nucleoplasm viscosity) regulated liquid–liquid phase separation mechanism of nucleolus formation and their multifunctional role shed light on other regulatory processes, apart from ribosomal biogenesis of the nucleolus. Using hepatocellular carcinoma as a model to study the role of nucleoli in tumor progression, we review the potential of nucleolus coalescence in the onset and development of tumors through non-ribosomal biogenesis pathways, thereby providing new avenues for early diagnosis and cancer therapy. Molecular-based classifications have failed to identify the nucleolar-based molecular targets that facilitate cell-cycle progression. However, the algorithm-based tumor risk identification with high-resolution medical images suggests prominent nucleoli, karyotheca, and increased nucleus/cytoplasm ratio as largely associated with tumor recurrence. Nonetheless, the role of the non-ribosomal functions of nucleoli in tumorigenesis remains elusive. This clearly indicates the lacunae in the study of the nucleolar proteins pertaining to cancer.日益增多的研究证据表明，核糖体生物发生增强、核仁（nucleolus）体积增大及核仁数量分布异常，均与转录失调密切相关，而后者会促使细胞发生异常增殖并最终恶变。核仁异常已被视作侵袭性肿瘤的预后性组织学标志物。近年来，学界对核仁形成的、受染色质网络（核质粘度）调控的液-液相分离机制，以及核仁除核糖体生物发生之外的多方面功能的认知不断深入，这为阐明其他调控过程提供了新的视角。本研究以肝细胞癌（hepatocellular carcinoma）为模型，探究核仁在肿瘤进展中的作用，综述了核仁融合通过非核糖体生物发生通路参与肿瘤发生与发展的潜在机制，从而为肿瘤早期诊断及癌症治疗开辟了新的研究方向。基于分子特征的肿瘤分型尚未能识别出可促进细胞周期进展的核仁相关分子靶点。然而，借助高分辨率医学影像的算法辅助肿瘤风险识别模型显示，核仁显著、核被膜（karyotheca）异常及核质比升高，均与肿瘤复发密切相关。尽管如此，核仁的非核糖体功能在肿瘤发生发展中的具体作用仍不甚明晰。这一现状清晰地揭示了当前癌症相关核仁蛋白研究领域尚存的研究空白。