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

Sequera, Celia; Manzano, Sara; Guerrero, Carmen; Porrás, Almudena

doi:10.2217/hep-2017-0026

Cited by 27 publications

(28 citation statements)

References 79 publications

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“…Moreover, over-expression of p87C3G isoform is associated with chronic myeloid leukemia development [ 31 ]. Our previous genomic and transcriptomic studies using available human cancer databases indicated that C3G mRNA levels are increased in HCC compared to a normal liver [ 32 ]. Furthermore, HCC patients bearing somatic mutations and other genetic alterations in C3G gene showed lower survival [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…Our previous genomic and transcriptomic studies using available human cancer databases indicated that C3G mRNA levels are increased in HCC compared to a normal liver [ 32 ]. Furthermore, HCC patients bearing somatic mutations and other genetic alterations in C3G gene showed lower survival [ 32 ]. Although these data suggest an implication of C3G in HCC, it remains unknown whether C3G is a positive or negative regulator of HCC cellular properties.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

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

Self Cite

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“…Several proteins deregulated in human cancers have been shown to affect centrosomal division and ciliogenesis (Bettencourt-Dias and Glover, 2007; Nigg and Holland, 2018; Plotnikova et al, 2008; Wang and Dynlacht, 2018; Gonczy, 2015). C3G has been implicated in tumorigenesis, with higher as well as lower levels seen in different cancers (Che et al, 2015; Guerrero et al, 1998; Gutiérrez-Berzal et al, 2006; Hirata et al, 2004; Okino et al, 2006; Priego et al, 2016; Radha et al, 2011; Samuelsson et al, 2011; Sequera et al, 2018). The function of C3G in regulating centrosome division may be responsible for its deregulation being associated with tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear functions like chromatin remodeling and splicing are regulated by C3G (Shakyawar et al, 2017; Shakyawar et al, 2018). In a cell and tissue type dependent manner, C3G functions to either increase or decrease cell proliferation, and altered C3G levels are associated with human tumors and other disorders (Che et al, 2015; Guerrero et al, 1998; Gutiérrez-Berzal et al, 2006; Hirata et al, 2004; Ishimaru et al, 1999; Okino et al, 2006; Radha et al, 2011; Samuelsson et al, 2011; Sequera et al, 2018; Voss et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

C3G (RapGEF1) localizes to the mother centriole and regulates centriole division and primary cilia dynamics

Radha

2019

Preprint

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C3G (RapGEF1), a negative regulator of β-catenin, plays a role in cell differentiation and is essential for early embryonic development in mice. In this study, we identify C3G as a centrosomal protein that regulates centriole division and primary cilia dynamics. C3G is present at the centrosome in interphase as well as mitotic cells, but is absent at the centrioles in differentiated myotubes. It interacts with, and co-localizes with cenexin in the mother centriole. Stable clone of cells depleted of C3G by CRISPR/Cas9 showed reduction in cenexin protein, and presence of supernumerary centrioles. Over-expression of C3G resulted in inhibition of centrosome division in normal and hydroxyurea treated cells. Proportion of ciliated cells is higher, and cilia length longer in C3G knockout cells. C3G inhibits cilia formation and length dependent on its catalytic activity. Unlike wild type cells, C3G depleted cells inefficiently retracted their cilia upon stimulation to reenter the cell cycle, and proliferated slowly, arresting in G1. We conclude that C3G inhibits centriole division and maintains ciliary homeostasis, properties that may be important for its role in embryonic development.Summary statementWe identify C3G as a centrosomal protein and regulator of centriole number, primary cilia length and resorption. These properties are important for its role in embryogenesis, and suggest that mutations in C3G could cause ciliopathies.

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“…Hence, the number of inhibitors identified for Rap1 are limited and have not progressed into clinical trials thus far. The inhibitors that target the small GTPases or indirect strategies involving GEF inhibitors or GAP activators were reported to have promising results in laboratory studies, but not during clinical trials [119]. In recent years, a combined structure-based virtual screening and high throughput screening utilizing fluorescent guanine nucleotide exchange assays discovered SOS1 inhibitor, a Ras GEF enzyme [120].…”

Section: Therapeutic Potential Of Rap1 Signaling In Cancersmentioning

confidence: 99%

The Role of Ras-Associated Protein 1 (Rap1) in Cancer: Bad Actor or Good Player?

et al. 2020

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Metastasis is known as the most life-threatening event in cancer patients. In principle, the immune system can prevent tumor development. However, dysfunctional T cells may fail to eliminate the tumor cells effectively and provide additional survival advantages for tumor proliferation and metastasis. Constitutive activation of Ras-associated protein1 (Rap1) has not only led to T cell anergy, but also inhibited autophagy and supported cancer progression through various oncogenic events. Inhibition of Rap1 activity with its negative regulator, Rap1GAP, impairs tumor progression. However, active Rap1 reduces tumor invasion in some cancers, indicating that the pleiotropic effects of Rap1 signaling in cancers could be cancer-specific. All in all, targeting Rap1 signaling and its regulators could potentially control carcinogenesis, metastasis, chemoresistance and immune evasion. Rap1GAP could be a promising therapeutic target in combating cancer.

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

Cited by 27 publications

References 79 publications

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

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

C3G (RapGEF1) localizes to the mother centriole and regulates centriole division and primary cilia dynamics

The Role of Ras-Associated Protein 1 (Rap1) in Cancer: Bad Actor or Good Player?

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