G-Protein-Coupled Receptor GPR49 is Up-regulated in Basal Cell Carcinoma and Promotes Cell Proliferation and Tumor Formation

Tanese, Keiji; Fukuma, Mariko; Yamada, Taketo; Mori, Taisuke; Yoshikawa, Tsutomu; Watanabe, Wakako; Ishiko, Akira; Amagai, Masayuki; Nishikawa, Takeji; Sakamoto, Michiie

doi:10.2353/ajpath.2008.071091

Cited by 133 publications

(130 citation statements)

References 28 publications

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“…We have shown that knockdown of Lgr5 results in a reduction in the tumourigenicity of colorectal cancer cells. This result is consistent with a previous report showing that human immortalized keratinocyte HaCaT cells overexpressing Lgr5 could form tumours when transplanted into immunodeficient mice 16 . Intriguingly, knockdown of Lgr5 caused a significant reduction in clonogenicity of DLD-1 cells, but did not affect their growth under adherent conditions.…”

Section: Discussionsupporting

confidence: 83%

“…It has been shown that Lgr5 is a Wnt target gene and is highly expressed in several tumour cell types, including colorectal cancer cells 1,16,17,33,34 . We have shown that knockdown of Lgr5 results in a reduction in the tumourigenicity of colorectal cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…LGR5 has been used as a stem cell marker of tissues where the regulation by Wnt signalling has a critical role. In addition, LGR5 has been reported to be upregulated in some cancer tissues, such as basal cell carcinomas, hepatocelluar carcinomas, ovarian tumours and colorectal tumours 16,17 . It has also been reported that Lgr5-positive intestinal stem cells are the cells of origin of adenoma initiated by mutations in adenomatous polyposis coli (APC).…”

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confidence: 99%

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The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

et al. 2014

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Aberrant activation of Wnt signalling results in colorectal tumours. Lgr5 is specifically expressed in stem cells of the intestine and has an essential role in maintaining tissue homeostasis. Lgr5-positive stem cells are responsible for the intestinal adenoma initiated by mutations in adenomatous polyposis coli. Furthermore, Lgr5 interacts with R-spondins and thereby activates Wnt signalling. However, the function of Lgr5 in colorectal tumourigenesis is unclear. Here we show that LGR5 is required for the tumourigenicity of colorectal cancer cells. We show that the transcription factor GATA6 directly enhances the expression of LGR5. We further demonstrate that GATA6 is upregulated in colorectal cancer cells due to the downregulation of miR-363, which directly targets GATA6. Moreover, we show that overexpression of miR-363 suppresses the tumourigenicity of colorectal cancer cells. These results suggest that the miR-363-GATA6-LGR5 pathway is critical for colorectal tumourigenesis and would be a promising target for the treatment of colorectal cancer.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

et al. 2014

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“…Some of these GPCRs have been linked to cancer development and progression on the basis of their overexpression and/or up-regulation by diverse factors [173][174][175] . For instance, an elevated expression of the orphan G-proteincoupled receptor GPR49 was involved in the formation and proliferation of basal cell carcinoma [176] , while GPR18 was found associated with melanoma metastases [177] . In lung, cervix, skin, urinary bladder, testis, head and neck squamous cell carcinomas were detected high levels of GPR87 [178,179] for which UDP-glucose, cysteinyl-leukotrienes and LPA exhibited binding properties [180] .…”

Section: Orphan Gpcrs and Cancermentioning

confidence: 99%

GPCRs and cancer

Lappano

2012

Acta Pharmacol Sin

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G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.

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“…LGR5 encodes a Gprotein coupled receptor possibly involved in tumor formation, 12 whereas PTPRR encodes a protein tyrosine phosphatase possibly involved in neuronal growth and differentiation. 13 TSPAN8 is a member of the tetraspanin transmembrane protein family.…”

Section: Introductionmentioning

confidence: 99%

Reduced body weight in male Tspan8-deficient mice

et al. 2010

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Objective: The gene TSPAN8 was recently identified in a genome-wide association study as the most likely causal gene in a locus that was correlated with the risk of type 2 diabetes (T2D) in northern European individuals. To assess whether Tspan8 is the actual T2D-causal gene in this locus, we ablated its expression in mice and determined the consequences of this ablation on a multitude of metabolic traits. Results: We found that genetic ablation of Tspan8 in mice results in a reduction (À15.6%) in the body weight of males fed a normal chow diet and that this deficiency results in a resistance to body weight gain (À13.7%) upon feeding a high fat and high carbohydrate diet. The differences in body weight could only be detected in male mice and were the consequence of both a decrease in fat deposition, and a decrease in lean body mass (16.9 and 11%, respectively). In spite of the significant body weight difference, no changes in fasting insulin and glucose levels could be detected in Tspan8 knockout mice, nor could we identify changes in the clearance of glucose or sensitivity to insulin in oral glucose tolerance test and intraperitoneal insulin sensitivity test studies, respectively. In addition, male Tspan8 knockout mice showed significantly lower bone mineral density and phosphorus levels (6.2 and 16.6%, respectively). Expression of Tspan8 in mouse was highest in digestive tissues, but virtually absent from the pancreas. In contrast, expression of human TSPAN8 was substantial in digestive tissues, as well as pancreatic cells. Conclusions: Our results argue for a role for Tspan8 in body-weight regulation in males, but do not show differences in T2D-associated traits that were anticipated from previous human genome-wide association studies. Differences in Tspan8 expression levels in mouse and human tissues suggest that Tspan8 could fulfill different or additional physiological functions in these organisms.

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G-Protein-Coupled Receptor GPR49 is Up-regulated in Basal Cell Carcinoma and Promotes Cell Proliferation and Tumor Formation

Cited by 133 publications

References 28 publications

The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

GPCRs and cancer

Reduced body weight in male Tspan8-deficient mice

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