Rap1‐suppressed tumorigenesis is concomitant with the interference in Ras effector signaling

Lin, Yea-Lih; Mettling, Clément; Chou, Chen‐Kung

doi:10.1016/s0014-5793(00)01150-9

Cited by 7 publications

(9 citation statements)

References 41 publications

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“…Moreover, in nude mice xenograft assays, Rap1 suppresses their intrinsic tumorigenic capacity [ 59 ]. Rap1 also acts as a suppressor of tumorigenesis by inhibiting TPA-(phorbol ester) or insulin-induced Ras/Raf/MEK/ERK activation and cell proliferation in Hep3B cells [ 60 ]. In contrast, experiments developed in other human liver cancer cell lines (HepG2, HepG2.2.15 and SMMC-7721) support the involvement of Rap1 in hepatitis B virus (HBV)-related HCC pathogenesis.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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“…However, there is no much information about Rap function in HCC, and that available is quite controversial [ 32 ]. Rap1 could suppress tumorigenesis in Hep3B cells [ 52 ] or contribute to HCC induction [ 53 ]. More recent studies reported an upregulation of either Rap2B or Rap1B [ 54 , 55 ] expression in HCC, associated with increased proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation

Sequera

Bragado

Manzano

et al. 2020

Cancers

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The complexity of hepatocellular carcinoma (HCC) challenges the identification of disease-relevant signals. C3G, a guanine nucleotide exchange factor for Rap and other Ras proteins, plays a dual role in cancer acting as either a tumor suppressor or promoter depending on tumor type and stage. The potential relevance of C3G upregulation in HCC patients suggested by database analysis remains unknown. We have explored C3G function in HCC and the underlying mechanisms using public patient data and in vitro and in vivo human and mouse HCC models. We found that C3G is highly expressed in progenitor cells and neonatal hepatocytes, whilst being down-regulated in adult hepatocytes and re-expressed in human HCC patients, mouse HCC models and HCC cell lines. Moreover, high C3G mRNA levels correlate with tumor progression and a lower patient survival rate. C3G expression appears to be tightly modulated within the HCC program, influencing distinct cell biological properties. Hence, high C3G expression levels are necessary for cell tumorigenic properties, as illustrated by reduced colony formation in anchorage-dependent and -independent growth assays induced by permanent C3G silencing using shRNAs. Additionally, we demonstrate that C3G down-regulation interferes with primary HCC tumor formation in xenograft assays, increasing apoptosis and decreasing proliferation. In vitro assays also revealed that C3G down-regulation enhances the pro-migratory, invasive and metastatic properties of HCC cells through an epithelial-mesenchymal switch that favors the acquisition of a more mesenchymal phenotype. Consistently, a low C3G expression in HCC cells correlates with lung metastasis formation in mice. However, the subsequent restoration of C3G levels is associated with metastatic growth. Mechanistically, C3G down-regulation severely impairs HGF/MET signaling activation in HCC cells. Collectively, our results indicate that C3G is a key player in HCC. C3G promotes tumor growth and progression, and the modulation of its levels is essential to ensure distinct biological features of HCC cells throughout the oncogenic program. Furthermore, C3G requirement for HGF/MET signaling full activation provides mechanistic data on how it works, pointing out the relevance of assessing whether high C3G levels could identify HCC responders to MET inhibitors.

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“…The first data were obtained from different human cancer databases and indicate that RAPGEF1 mRNA levels increase in samples from HCC patients and in patient-derived xenografts, as compared to non-pathological liver samples [23] . Later, new analyses of cancer databases revealed that RAPGEF1 mRNA levels gradually increase in HCC patients as the disease progresses (from stages I to III), being also higher in HCC cell lines as compared to adult hepatocytes [46] [Table 1]. This increase in C3G levels is associated with a lower survival [46] , as is the presence of somatic mutations and other genetic alterations in RAPGEF1 gene (amplification, deletion, etc.)…”

Section: C3g and Other Ras Gefs In Liver Cancermentioning

confidence: 99%

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

Porrás¹,

Sequera²,

Bragado³

et al. 2021

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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

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Rap1‐suppressed tumorigenesis is concomitant with the interference in Ras effector signaling

Cited by 7 publications

References 41 publications

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

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

C3G Is Upregulated in Hepatocarcinoma, Contributing to Tumor Growth and Progression and to HGF/MET Pathway Activation

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

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