Contribution of C3G and other GEFs to liver cancer development and progression

• DOI: 10.20517/2394-5079.2021.16
• Publication Date: 2021-05-18T10:39:47Z
• Authors: Almudena Porras; Celia Sequera; Paloma Bragado; Alvaro Gutierrez-...; Carmen Guerrero
• Keywords: Cholangiocarcinoma; 0301 basic medicine; Hepatocarcinoma; 03 medical and health sciences; RAPGEF1; CRK; C3G; Rap; Rho GEFs; Liver cancer; Ras GEFs; 3. Good health

© The Author(s) 2021.<br/>The work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2016-76588-C2-1-R and PID2019-104143RB-C22 to Porras A; and SAF2016-76588-C2-2-R and PID2019-104143RB-C21 to Guerrero G and PID2019-104991RB-I00 to Bragado P), and by two grants from the Council of Education of Junta de Castilla y León, Spain (SA017U16 and SA078P20 to Guerrero C). All funding was cosponsored by the European FEDER Program. Sequera C was supported by a fellowship from Complutense University from Madrid. Gutierrez-Uzquiza A is supported by Madrid Community Program for Talent Attraction (MRF 2017-T1/BMD-5468). Bragado P received support from BBVA (Becas Leonardo 2018, BBM-TRA-0041).<br/>Primary liver cancers constitute the fourth leading cause of cancer mortality worldwide, due to their high morbidity, late diagnosis and lack of effective treatments. Hepatocellular carcinoma (HCC) represents 80% and cholangiocarcinoma (CCA) 15% of liver cancers. Several genetic and epigenetic gene alterations (e.g., TERT, TP53 or CTNNB1) are HCC drivers, although many additional gene alterations contribute to HCC initiation and/or progression. Rho and Ras GTPases have been widely implicated in tumorigenesis and their activators (GEFs) have recently emerged as putative key players in liver cancer. The Ras GEF, C3G (RAPGEF1), a GEF mainly for Rap proteins, has recently been uncovered as a relevant gene in HCC. Its upregulation promotes tumor growth, although a decrease in C3G levels favors migration/invasion and lung metastasis. Rap1A/1B/2A/2B are overexpressed in HCC tumors, but their effects are controversial and not equivalent to those of C3G. The C3G partner, CRKL, is also overexpressed in HCC, promoting proliferation, migration and invasion. Various Rho GEFs are also deregulated in liver cancer. Tiam1 and Tiam2 expression is upregulated in HCC, promoting proliferation, migration and metastasis. In addition, ARHGEF-10L/9/19/39 are overexpressed in HCC tumors, facilitating migration, invasion, metastasis and proliferation. Another Rho GEF, Vav2, is also involved in metastasis. Little is known about the participation of these GEFs and GTPases in CCA. However, analysis of cancer databases uncovered deregulations or genetic alterations in several of these genes, in both CCA and HCC. Hence, GEFs function appear essential for liver homeostasis, although future studies are needed to define their precise function in liver cancer.<br/>