Gramantieri Laura, Giovannini Catia, Piscaglia Fabio, Fornari Francesca
Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
J Hepatocell Carcinoma. 2021 May 12;8:369-385. doi: 10.2147/JHC.S268292. eCollection 2021.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers helping patient allocation to the best therapeutic option contribute to poor prognosis in advanced stages. MicroRNAs' (miRNAs) deregulated expression contributes to tumor development and progression and influences drug resistance in HCC. Accordingly, miRNAs have been extensively investigated as both biomarkers and therapeutic targets. The diagnostic and prognostic roles of circulating miRNAs have been ascertained, though with some inconsistencies across studies. From a therapeutic perspective, miRNA-based approaches demonstrated safety profiles and antitumor efficacy in HCC animal models. Nevertheless, caution should be used when transferring preclinical findings to the clinic, due to possible molecular inconsistency between animal models and the heterogeneous patterns of human diseases. A wealth of information is offered by preclinical studies exploring the mechanisms driving miRNAs' aberrant expression, the molecular cascades triggered by miRNAs and the corresponding phenotypic changes. Ex-vivo analyses confirmed these results, further shedding light on the intricacy of the human disease often overcoming pre-clinical models. This complexity seems to be ascribed to the intrinsic heterogeneity of HCC, to different risk factors driving its development, as well as to changes across stages and previous treatments. Preliminary findings suggest that miRNAs associated with specific risk factors might be more informative in defined patients' subgroups. The first issue to be considered when trying to envisage a possible translational perspective is the molecular context that often drives different miRNA functions, as clearly evidenced by "dual" miRNAs. Concerning the possible roles of miRNAs as biomarkers and therapeutic targets, we will focus on miRNAs' involvement in metabolic pathways and in the modulation of tumor microenvironment, to support their exploitation in defined contexts.
肝细胞癌（HCC）是癌症相关死亡的第二大主要原因。分子异质性以及缺乏有助于患者选择最佳治疗方案的生物标志物导致晚期预后不良。微小RNA（miRNA）的表达失调促进了肝癌的发生和发展，并影响其耐药性。因此，miRNA作为生物标志物和治疗靶点都受到了广泛研究。循环miRNA的诊断和预后作用已得到证实，尽管各研究之间存在一些不一致。从治疗角度来看，基于miRNA的方法在HCC动物模型中显示出安全性和抗肿瘤疗效。然而，由于动物模型与人类疾病的异质性模式之间可能存在分子不一致性，在将临床前研究结果转化到临床时应谨慎。临床前研究提供了大量信息，探索了驱动miRNA异常表达的机制、miRNA触发的分子级联反应以及相应的表型变化。体外分析证实了这些结果，进一步揭示了人类疾病的复杂性，这种复杂性往往超越临床前模型。这种复杂性似乎归因于HCC的内在异质性、驱动其发展的不同风险因素以及不同阶段和既往治疗的变化。初步研究结果表明，与特定风险因素相关的miRNA在特定患者亚组中可能更具信息价值。在设想可能的转化前景时首先要考虑的问题是分子背景，它常常驱动不同的miRNA功能，“双重”miRNA就清楚地证明了这一点。关于miRNA作为生物标志物和治疗靶点的可能作用，我们将重点关注miRNA在代谢途径中的作用以及对肿瘤微环境的调节作用，以支持其在特定背景下的应用。
