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CG7379/ING1 in cancer progression. A study of migration and invasion in in vivo and in vitro epithelial systems

ABSTRACT: Metastasis is the leading cause of death for cancer patients. Consequently it is imperative that we improve our understanding of the molecular mechanisms that underlie progression of tumour growth towards malignancy. A large-scale genetic screen was carried out to identify genes that affect tumour progression in the living fly. This screen identified CG7379 as promoting cancer cell invasion when gene expression was knocked down in epithelial tumours in the dorsal thorax of the fly. The uncharacterised CG7379 Drosophila gene shows high homology with the human ING (inhibitor of growth) gene family. ING proteins are known to be involved in the control of cell proliferation, senescence and apoptosis. However, their potential role in cell migration and invasion is yet to be properly documented. Homeostasis of epithelial tissues relies on the control of cell polarity and architecture, and our results strongly suggest that CG7379 and ING1 play an important role in cell-cell junction integrity maintenance. The knockdown of both the Drosophila and human gene increases invasion in the living animal and in in vitro invasion assays respectively and gene knock-down led to severe disruption of cell-cell junction integrity. We used Clariom™ S Assay arrays to detail the global programme of gene expression following ING1 KD to detect DEG involved in regulation of cell motility and cell-cell junction assembly and maintenance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125438 | GEO | 2021/09/22

REPOSITORIES: GEO

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Project description:Invasion of lymphatic vessels is a key step in the metastasis of primary tumour cells to draining lymph nodes. Recent evidence indicates that such metastasis can be facilitated by tumour lymphangiogenesis, although it remains unclear whether this is a consequence of increased lymphatic vessel numbers or alteration in the properties of the vessels themselves. Here we have addressed this important question by comparing the RNA profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T-241/VEGF-C metastatic fibrosarcoma. Our findings reveal significant changes in the expression of some 792 genes in tumour lymphatics (â?¥ 2 fold up/downregulation, p â?¤ 0.05), involving particularly transcripts associated with junctional adhesion, immunomodulation, extracellular matrix and vessel growth/patterning, several of which we have confirmed by RT-PCR and/or immunohistochemistry. Interestingly, this altered phenotype could not be attributed solely to VEGF-C induced lymphoproliferation, as no similar change in gene expression was reported when human LEC were cultured with VEGF-C in vitro. Moreover, we show that a key protein upregulated in the mouse model, namely the tight junction protein Endothelial Cell Specific Adhesion Molecule (ESAM), is similarly upregulated in tumour lymphatic vessels from 2/2 patients with head and neck squamous cell carcinoma and 4/4 patients with aggressive bladder carcinoma. These findings demonstrate a previously unrecognized influence of tumour environment on lymphatic gene expression and identify candidate tumour specific vessel markers that may prove valuable for either prognosis or therapy. Experiment Overall Design: Here we have investigated the invasion of lymphatic vessels as a key step in the metastasis of primary tumour cells to draining lymph nodes by comparing the gene expression profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T241/VEGF-C/GFP metastatic fibrosarcoma. Three biological replicates were analyzed from each group.

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CG7379/ING1 in cancer progression. A study of migration and invasion in in vivo and in vitro epithelial systems

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