Marin Jose J G, Reviejo Maria, Soto Meraris, Lozano Elisa, Asensio Maitane, Ortiz-Rivero Sara, Berasain Carmen, Avila Matias A, Herraez Elisa
Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute for Biomedical Research of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain.
Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain.
Cancers (Basel). 2021 Dec 21;14(1):18. doi: 10.3390/cancers14010018.
The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.
全球范围内发病率不断上升的两种最常见的原发性肝癌是肝细胞癌（HCC）和肝内胆管癌（iCCA），它们是五年生存率极低的五种最致命实体瘤之一。大多数病例早期诊断困难、两种肿瘤侵袭性强，且对经典化疗或现代靶向治疗等药物治疗反应不佳，这些因素导致了这些患者的不良预后。前体mRNA成熟过程中的可变剪接（AS）会导致一些变化，这些变化可能会影响参与癌症生物学不同方面的蛋白质，如细胞周期失调、细胞骨架紊乱、迁移和黏附，从而促进致癌作用、肿瘤进展，使癌细胞逃避药物治疗。导致癌症相关异常剪接的原因包括产生或破坏剪接位点或剪接增强子或沉默子的突变、剪接因子的异常表达以及影响剪接机制活性的信号通路受损。在此，我们回顾了关于可变剪接对肝癌发生以及肝细胞癌和肝内胆管癌恶性特征发展影响的现有信息，要开发旨在操纵癌细胞表型的新型治疗方法，就需要了解这些信息。
