GPR48, a poor prognostic factor, promotes tumor metastasis and activates β-catenin/TCF signaling in colorectal cancer

Wu, Jinhua; Xie, Na; Xie, Ke; Zeng, Jun; Cheng, Lin; Y, Lei; Liu, Yuan; Li, Song; Dong, Di; Chen, Yi; Zeng, Rui; Nice, Edouard C.; Huang, Canhua; Wei, Yuquan

doi:10.1093/carcin/bgt229

Cited by 42 publications

(49 citation statements)

References 47 publications

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“…4,5 These results are not surprising, because GPCRs have the ability to use alternative For 47 and it is likely that these 2 GPCRs regulate distinct functional programs downstream of b-catenin through their respective signaling cascade in colon cancer. Furthermore, using clinically available Cox inhibitors, we and others have previously shown that inhibition of Cox suppresses b-catenin activation and has a profound effect on LSC functions in AML initiated by MLL-AF9 or AML1-ETO.…”

Section: Discussionmentioning

confidence: 95%

“…G protein-coupled receptors (GPCRs), the largest family of cell-surface molecules with key roles in transmitting signals to downstream effectors, have emerged as crucial players in promoting tumor growth and metastasis 1,[4][5][6][7][8] and represent one of the most important drug targets in pharmaceutical development. 9,10 Recent evidence indicates that GPCRs are active in various cancer cell lines and primary patient samples, 7,8 and that oncogenic GPCRs augment activation of b-catenin signaling in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…4,7,11 The importance of GPCRs in regulation of b-catenin signaling and tumorigenesis has been increasingly recognized. 4,5,7,9 A recent report has identified GPR84 (a proinflammatory GPCR) 12 as an LSC-specific gene with its expression level significantly higher in human AML LSCs than that in HSCs in a genome-wide gene-expression analysis and subsequent quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR). 13 Interestingly, the high level of GPR84 expression is also observed exclusively in human AML-M5 LSCs compared with other LSCs and HSCs, 14 indicating a possible disease subtype-dependent expression.…”

Section: Introductionmentioning

confidence: 99%

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GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis

Dietrich

Yang

Leung

et al. 2014

Blood

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Key Points• GPR84 simultaneously augments b-catenin signaling and an oncogenic transcription program essential for establishment of MLL.• Our study demonstrates a strong dependence of hematopoietic stem cell-derived MLL leukemic cells on GPR84 for disease maintenance in vivo.b-catenin is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). Targeted inhibition of b-catenin signaling has been hampered by the lack of pathway components amenable to pharmacologic manipulation. Here we identified a novel b-catenin regulator, GPR84, a member of the G protein-coupled receptor family that represents a highly tractable class of drug targets. High GPR84 expression levels were confirmed in human and mouse AML LSCs compared with hematopoietic stem cells (HSCs). Suppression of GPR84 significantly inhibited cell growth by inducing G1-phase cell-cycle arrest in pre-LSCs, reduced LSC frequency, and impaired reconstitution of stem cell-derived mixed-lineage leukemia (MLL) AML, which represents an aggressive and drug-resistant subtype of AML. The GPR84-deficient phenotype in established AML could be rescued by expression of constitutively active b-catenin. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a-transduced stem cells. Microarray analysis demonstrated that GPR84 significantly upregulated a small set of MLL-fusion targets and b-catenin coeffectors, and downregulated a hematopoietic cell-cycle inhibitor. Altogether, our data reveal a previously unrecognized role of GPR84 in maintaining fully developed AML by sustaining aberrant b-catenin signaling in LSCs, and suggest that targeting the oncogenic GPR84/b-catenin signaling axis may represent a novel therapeutic strategy for AML. (Blood. 2014;124(22):3284-3294) IntroductionThe ability for self-renewal, migration/invasion, and drug resistance are fundamental properties of malignant stem cells that drive both disease progression and relapse. Identification of pathways and their molecular components essential for the regulation of abnormally acquired stem cell-like properties is a prerequisite for understanding the underlying mechanisms of oncogenesis and designing effective anticancer therapeutic strategies. We and others have previously shown that mixed-lineage leukemia (MLL) fusion proteins can aberrantly activate Wnt/b-catenin signaling in hematopoietic stem cells (HSCs) or more differentiated granulocyte-macrophage progenitors (GMPs) for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia subtype M5 (AML-M5) 1,2 ; however, the mechanisms involved remain obscure. It has also been noted that activation of b-catenin is observed in tumors without clear mutations in major components of this pathway or an increase in Wnt signaling.3 This suggests that other developmental signaling pathways may be capable of inducing activation or downstream signaling of b-catenin.G protein-coupled receptors (GPCRs), the largest family of cell-surface molecules with key roles in transmitting signals to downstream effectors, ...

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis

Dietrich

Yang

Leung

et al. 2014

Blood

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“…Stimulation of the Wnt/β-catenin and Ras oncogene by P21-activated kinase 1 increases the progression of CRC and enhances survival by the stimulation of hypoxia-inducible factor 1α and β-catenin (19). In another study, Wu et al (20) showed that β-catenin increased T-cell factor 4 (TCF4) transcription activity and expression of its target genes, including cyclin D1 and c-Myc, in CRC cells. Correlation analysis showed that β-catenin expression in CRC tissues was positively associated with c-Myc expression.…”

Section: Discussionmentioning

confidence: 99%

FBXL20 acts as an invasion inducer and mediates E-cadherin in colorectal adenocarcinoma

et al. 2014

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The mechanisms eliciting colorectal adenocarcinoma are not well understood and the FBXL20 gene is problematic as it exhibits an abnormal expression in colorectal cancer cells. In the present study a recombinant plasmid, pReceiver-M03-FBL20 expression plasmid was constructed, which overexpressed FBXL20; this was transfected into Lovo cells to form Lovo-FBL20 cells. The FBXL20 expression level was examined by quantitative polymerase chain reaction (qPCR) and western blot analysis. The cell viability and invasion capacity were measured using cell counting kit 8, Transwell chamber and wound healing assays, respectively. The associated genes, including E-cadherin, β-catenin, c-Myc, SET nuclear oncogene, protein phosphatase-2A, Axin, p53 and caspase 3, were detected by qPCR and western blotting. It was demonstrated that the FBXL20 expression level was markedly upregulated in the Lovo-FBL20 cells transfected with pReceiver-M03-FBL20 expression plasmid, compared with that of the Lovo cells. In addition, the cell viability and invasion capacity of the Lovo-FBL20 cells were significantly increased. These increases correlated with a significant upregulation in the expression level of β-catenin and c-Myc, and a downregulated expression level of E-cadherin. The results of the present study indicate that FBXL20 may mediate the ubiquitin degradation of E-cadherin resulting in an increased invasive ability of malignant cells.

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“…In the case of skin and prostate, LGR4 promotes tumorigenesis by modulating MEK/ERK and Wnt/β−catenin pathways and the PI3K/Akt cascade, respectively [98,99]. In colorectal cancer, LGR4 expression is markedly upregulated in moderately and poorly differentiated cells as well as at the tumor invasive front and in metastasis and it significantly correlates with nodal spread in gastric cancer [100][101][102]. Altogether, studies point LGR4 as a poor-prognosis factor.…”

Section: Prognostic Value Of Lgrsmentioning

confidence: 97%

LGRs receptors as peculiar GPCRs involved in cancer

Garcia¹

2017

J Stem Cell Res Med

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G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in mammalian genomes. The Leucine-rich repeat-containing G protein-coupled receptors LGR4, LGR5 and LGR6 belong to the type A rhodopsin-like family and are closely structurally related to the glycoprotein hormone receptors. They have the particularity to be expressed in stem/progenitor cells.LGRs commonly recognize R-spondins as ligands leading to Wnt signaling regulation. Whereas LGR4 plays an essential role during development and adult homeostasis and exerts a dominant function over its paralogues, the function of LGR5 still remains controversial. In cancer cells, LGRs identify tumor-initiating cells and their expression can be correlated with tumor stage and prognosis. The molecular events underlying deregulated expression of LGRs in cancer cells and potential new therapeutic approaches to target cancer cells are reviewed.

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GPR48, a poor prognostic factor, promotes tumor metastasis and activates β-catenin/TCF signaling in colorectal cancer

Cited by 42 publications

References 47 publications

GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis

GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis

FBXL20 acts as an invasion inducer and mediates E-cadherin in colorectal adenocarcinoma

LGRs receptors as peculiar GPCRs involved in cancer

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