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Hepat Oncol. 2018 Apr 16;5(1):HEP05. doi: 10.2217/hep-2017-0026. eCollection 2018 Jan.

How Rap and its GEFs control liver physiology and cancer development. C3G alterations in human hepatocarcinoma.

Sequera C1,2,1,2, Manzano S1,2,1,2, Guerrero C3,4,5,3,4,5, Porras A1,2,1,2.

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Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
Instituto de Biología Molecular y Celular del Cáncer, USAL-CSIC, Salamanca, Spain.
Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.


Rap proteins regulate liver physiopathology. For example, Rap2B promotes hepatocarcinoma (HCC) growth, while Rap1 might play a dual role. The RapGEF, Epac1, activates Rap upon cAMP binding, regulating metabolism, survival, and liver regeneration. A liver specific Epac2 isoform lacking cAMP-binding domain also activates Rap1, promoting fibrosis in alcoholic liver disease. C3G (RapGEF1) is also present in the liver, but mainly as shorter isoforms. Its function in the liver remains unknown. Information from different public genetic databases revealed that C3G mRNA levels increase in HCC, although they decrease in metastatic stages. In addition, several mutations in RapGEF1 gene are present, associated with a reduced patient survival. Based on this, C3G might represent a new HCC diagnostic and prognostic marker, and a therapeutic target.


C3G; Epac; Rap; hepatocarcinoma; liver; liver diseases

Conflict of interest statement

Financial & competing interests disclosure This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2016-76588-C2-1-R to A Porras and SAF2016-76588-C2-2-R to C Guerrero), two grants from the Council of Education of Junta de Castilla y León, Spain (SA157A12-1 and SA017U16 to C Guerrero) and by a grant from the Council of Health of Junta de Castilla y León, Spain (GRS 991/A/14 to FMH). All funding was cosponsored by the European FEDER Program. C Sequera and S Manzano are recipients of PhD fellowships from Complutense University of Madrid and Spanish Ministry of Education, respectively. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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