Splicing alterations in pancreatic ductal adenocarcinoma: a new molecular landscape with translational potential

被引:0
作者
Emilia Alors-Pérez
Sergio Pedraza-Arevalo
Ricardo Blázquez-Encinas
María Trinidad Moreno-Montilla
Víctor García-Vioque
Inmaculada Berbel
Raúl M. Luque
Bruno Sainz
Alejandro Ibáñez-Costa
Justo P. Castaño
机构
[1] Maimonides Biomedical Research Institute of Córdoba (IMIBIC),Department of Cell Biology, Physiology, and Immunology
[2] University of Córdoba,Department of Cancer Biology
[3] Reina Sofía University Hospital (HURS),Cancer Stem Cells and Fibroinflammatory Microenvironment Group
[4] Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición,undefined
[5] (CIBERObn),undefined
[6] Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM,undefined
[7] Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS),undefined
[8] Gastrointestinal Tumours Research Programme,undefined
[9] Biomedical Research Network in Cancer (CIBERONC),undefined
来源
Journal of Experimental & Clinical Cancer Research | / 42卷
关键词
Pancreatic cancer; Splicing; Splicing machinery; Splicing isoforms; Splicing modulation;
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摘要
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers worldwide, mainly due to its late diagnosis and lack of effective therapies, translating into a low 5-year 12% survival rate, despite extensive clinical efforts to improve outcomes. International cooperative studies have provided informative multiomic landscapes of PDAC, but translation of these discoveries into clinical advances are lagging. Likewise, early diagnosis biomarkers and new therapeutic tools are sorely needed to tackle this cancer. The study of poorly explored molecular processes, such as splicing, can provide new tools in this regard. Alternative splicing of pre-RNA allows the generation of multiple RNA variants from a single gene and thereby contributes to fundamental biological processes by finely tuning gene expression. However, alterations in alternative splicing are linked to many diseases, and particularly to cancer, where it can contribute to tumor initiation, progression, metastasis and drug resistance. Splicing defects are increasingly being associated with PDAC, including both mutations or dysregulation of components of the splicing machinery and associated factors, and altered expression of specific relevant gene variants. Such disruptions can be a key element enhancing pancreatic tumor progression or metastasis, while they can also provide suitable tools to identify potential candidate biomarkers and discover new actionable targets. In this review, we aimed to summarize the current information about dysregulation of splicing-related elements and aberrant splicing isoforms in PDAC, and to describe their relationship with the development, progression and/or aggressiveness of this dismal cancer, as well as their potential as therapeutic tools and targets.
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