c-Src Recruitment is Involved in c-MET-Mediated Malignant Behaviour of NT2D1 Non-Seminoma Cells

Leonetti, Erica; Gesualdi, Luisa; Scheri, Katia Corano; Dinicola, Simona; Fattore, Luigi; Masiello, Maria Grazia; Cucina, Alessandra; Mancini, Rita; Bizzarri, Mariano; Ricci, Giulia; Catizone, Angela

doi:10.3390/ijms20020320

Cited by 8 publications

(30 citation statements)

References 56 publications

(78 reference statements)

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“…Furthermore, the author found highest levels of c‐MET protein in non‐seminoma lesions compared with the GCNIS and seminoma samples (Scheri et al ., ). In a recent work, this research group has reported that inhibition of c‐Src resulted in abrogating HGF‐dependent NT2D1 cell proliferation, migration and invasion (Leonetti et al ., ). C‐Src, a proto‐oncogene, has been shown to be activated by c‐MET (Patel et al ., ), and this study indicates that c‐Scr is involved in c‐MET‐mediated malignancy in non‐seminoma.…”

Section: C‐met Signallingmentioning

confidence: 97%

Functions of genes related to testicular germ cell tumour development

2019

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Objective: Testicular germ cell tumour (TGCT) is a malignancy with a high heritable component. The inherited risk is polygenic, and around 50 susceptibility genes are identified. The functional role of the gene products for TGCT development is not well understood. The focus of this review is functional studies of genetic risk factors for TGCT derived from GCNIS and the signalling pathways involved in the pathogenesis. Recent developments: Genome-wide association studies have identified new risk loci for TGCT and confirmed previously identified susceptibility genes. Many of these risk genes are related to male germ cell development, sex determination and genomic integrity. Gain-and loss-of-function studies in animal models and TGCT cell lines, as well as gene and protein expression studies in TGCT patient samples, have contributed to the understanding of TGCT development. KITLG-KIT signalling is of crucial importance, but several other signal transduction pathways may also play a role. Many of the risk loci are in non-coding regions, and studies have revealed that non-coding RNAs may act as oncogenes or tumour suppressors in TGCT development. Conclusions: The risk of TGCT is polygenic, and the underlying molecular mechanisms are complex. Several signalling pathways are related to TGCT development, and both proteins and non-coding RNAs may act as oncogenes or tumour suppressors. Epigenetic studies are of importance to get further knowledge about how the signalling pathways are regulated. Hypermethylation of the 5' CpG island of the gene encoding the serine protease Testisin promotes its loss in testicular tumorigenesis. Br J Cancer 92, 760-769. Manuylov NL, Fujiwara Y, Adameyko II, Poulat F & Tevosian SG. (2007) The regulation of Sox9 gene expression by the GATA4/FOG2 transcriptional complex in dominant XX sex reversal mouse models. Dev Biol 307, 356-367.

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Section: C‐met Signallingmentioning

confidence: 97%

Functions of genes related to testicular germ cell tumour development

2019

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“…Changes in the structure of nuclear compartment are frequently observed during transcription, cell differentiation, senescence, cell cycle and tumorigenesis [49], and evidence of active nuclear Src has been reported in different contexts. A study carried out on NT2D1 non-seminoma fibroblasts reveals that Src phosphorylation is constitutively present in the nuclei of these cells, representing a downstream effector of c-MET pathway [50]. c-MET is the membrane receptor of HGF (Hepatocyte Growth Factor).…”

Section: Regulation Of Gene Transcription and Chromatin Architecturementioning

confidence: 99%

“…c-MET recruits Src when activated by HGF, and this stimulus seems to be a key point allowing Src to translocate into the nucleus where it interacts with some gene promoters. In this context, a pivotal role is played by the cancer microenvironment, given that in the culture basal conditions (without administration of HGF) the inhibition of Src causes the augment of invasiveness but decreases the cell proliferation rate and migration capability of mouse NT2D1 fibroblasts independently from c-MET pathway, may be due to the Src recruitment by other homeostatic pathways controlling the aggressiveness of these cells [50].…”

Section: Regulation Of Gene Transcription and Chromatin Architecturementioning

confidence: 99%

Nuclear Functions of the Tyrosine Kinase Src

Bagnato

Leopizzi²,

Urciuoli

et al. 2020

IJMS

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Src is the representative member of the Src-family kinases (SFKs), a group of tyrosine kinases involved in several cellular processes. Its main function has been for long confined to the plasma membrane/cytoplasm compartment, being a myristoylated protein anchored to the cell membrane and functioning downstream to receptors, most of them lacking intrinsic kinase activity. In the last decades, new roles for some SFKs have been described in the nuclear compartment, suggesting that these proteins can also be involved in directly regulating gene transcription or nucleoskeleton architecture. In this review, we focused on those nuclear functions specifically attributable to Src, by considering its function as both tyrosine kinase and adapting molecule. In particular, we addressed the Src involvement in physiological as well as in pathological conditions, especially in tumors.

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“…We also demonstrated that c-Src inhibition abrogates the HGF-dependent increase of cell proliferation, polarized and collective migration, as well as cell invasion [ 9 ]. In the same paper, we found that, in basal culture conditions, c-Src inhibition decreases the cell proliferation rate of NT2D1 cells, independently from c-MET pathway activation, indicating that c-Src is used by other constitutively activated pathways that are responsible of activation of the cell cycle.…”

Section: Introductionmentioning

confidence: 99%

“…In the same paper, we found that, in basal culture conditions, c-Src inhibition decreases the cell proliferation rate of NT2D1 cells, independently from c-MET pathway activation, indicating that c-Src is used by other constitutively activated pathways that are responsible of activation of the cell cycle. Notably, we also found that c-Src inhibition, when administered in basal culture conditions, increases NT2D1 invasiveness via a HGF-independent way, highlighting the importance of the microenvironmental cues in modulating cellular responses to pharmacological stimuli [ 9 ]. All together, these observations led us to further investigate the c-MET-triggered signal transduction pathway in non-seminoma cell malignant behavior.…”

Section: Introductionmentioning

confidence: 99%

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

Gesualdi

Leonetti

Cucina

et al. 2020

IJMS

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Overactivation of the c-MET/HGF system is a feature of many cancers. We previously reported that type II testicular germ cell tumor (TGCT) cells express the c-MET receptor, forming non-seminomatous lesions that are more positive compared with seminomatous ones. Notably, we also demonstrated that NT2D1 non-seminomatous cells (derived from an embryonal carcinoma lesion) increase their proliferation, migration, and invasion in response to HGF. Herein, we report that HGF immunoreactivity is more evident in the microenvironment of embryonal carcinoma biopsies with respect to seminomatous ones, indicating a tumor-dependent modulation of the testicular niche. PI3K/AKT is one of the signaling pathways triggered by HGF through the c-MET activation cascade. Herein, we demonstrated that phospho-AKT increases in NT2D1 cells after HGF stimulation. Moreover, we found that this pathway is involved in HGF-dependent NT2D1 cell proliferation, migration, and invasion, since the co-administration of the PI3K inhibitor LY294002 together with HGF abrogates these responses. Notably, the inhibition of endogenous PI3K affects collective cell migration but does not influence proliferation or chemotactic activity. Surprisingly, LY294002 administered without the co-administration of HGF increases cell invasion at levels comparable to the HGF-administered samples. This paradoxical result highlights the role of the testicular microenvironment in the modulation of cellular responses and stimulates the study of the testicular secretome in cancer lesions.

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c-Src Recruitment is Involved in c-MET-Mediated Malignant Behaviour of NT2D1 Non-Seminoma Cells

Cited by 8 publications

References 56 publications

Functions of genes related to testicular germ cell tumour development

Functions of genes related to testicular germ cell tumour development

Nuclear Functions of the Tyrosine Kinase Src

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

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