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

Abstract

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

C3G down-regulation enhances pro-migratory and stemness properties of oval cells by promoting an epithelial-mesenchymal-like process

“…C3G is expressed in mouse embryonic liver, where an enrichment in shorter isoforms, as compared to brain, was described 22 . We also found that C3G main isoform is expressed in neonatal and adult hepatocytes, as well as in oval cells, but at different levels 23 , 24 . Thus, C3G protein levels are high in both oval cells and neonatal hepatocytes, but low in adult hepatocytes.…”

Reviewing Advances in Understanding and Targeting the Mapk Signaling Pathway in Hepatocellular Carcinoma Progression and Therapeutics

“…The members of the RASGEFs are SOS, RAPGEF2, RASGRF2, RASGRP1, and RASGRP4. Of these, RASGRP1 was shown to be much more expressed in HCC as compared to the tissues around the tumor, and this high expression was found to be strongly correlated with the size and stage of the tumor (Porras et al 2021). Furthermore, it was discovered by multivariate analysis that RASGRP1 expression constituted a separate risk factor for the advancement of HCC (Porras et al 2021;.…”

“…Of these, RASGRP1 was shown to be much more expressed in HCC as compared to the tissues around the tumor, and this high expression was found to be strongly correlated with the size and stage of the tumor (Porras et al 2021). Furthermore, it was discovered by multivariate analysis that RASGRP1 expression constituted a separate risk factor for the advancement of HCC (Porras et al 2021;. Furthermore, SOS was shown to be a critical molecule implicated in many pathways triggered in HCC, indicating its carcinogenic function in the disease.…”